Acyclic Ikur inhibitors

ABSTRACT

A compound of formula I  
                 
 
wherein R 1 , R 2 , R 3 , R 4  and R 5  are described herein.

RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application No.60/715,679, filed on Sep. 9, 2005, incorporated herein by reference inits entirety.

FIELD OF THE INVENTION

The present invention provides for acyclic compounds useful asinhibitors of potassium channel function (especially inhibitors of theK_(v)1 subfamily of voltage gated K⁺ channels, more especiallyinhibitors of K_(v)1.5 (which have been linked to the ultra-rapidlyactivating delayed rectifier K⁺ current I_(Kur)), and/or K_(v)1.3channels, and/or K_(v)1.1 channels) and to pharmaceutical compositionscontaining such compounds. The present invention further provides formethods of using such compounds in the treatment and prevention ofarrhythmia, I_(Kur)-associated disorders, and other disorders mediatedby ion channel function.

BACKGROUND OF THE INVENTION

The ultra-rapidly activating delayed rectifier K⁺ current (I_(Kur)) isbelieved to represent the native counterpart to a cloned potassiumchannel designated K_(v)1.5 and, while present in human atrium, itappears to be absent in human ventricle. Furthermore, because of itsrapidity of activation and limited slow inactivation, I_(Kur) isbelieved to contribute significantly to repolarization in human atrium.Consequently, a specific blocker of I_(Kur), that is a compound whichblocks K_(v)1.5, would overcome the short coming of other compounds byprolonging refractoriness by retarding repolarization in the humanatrium without causing the delays in ventricular repolarization thatunderlie arrhythmogenic after depolarizations and acquired long QTsyndrome observed during treatment with current Class III antiarrhythmicagents. (Antiarrhythmic agents of Class III are drugs that cause aselective prolongation of the duration of the action potential withoutsignificant cardiac depression.)

Immunoregulatory abnormalities have been shown to exist in a widevariety of autoimmune and chronic inflammatory diseases, includingsystemic lupus erythematosis, chronic rheumatoid arthritis, type I andII diabetes mellitus, inflammatory bowel disease, biliary cirrhosis,uveitis, multiple sclerosis and other disorders such as Crohn's disease,ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis,ichthyosis, Graves ophthalmopathy and asthma. Although the underlyingpathogenesis of each of these conditions may vary, they have in commonthe appearance of a variety of auto-antibodies and self-reactivelymphocytes. Such self-reactivity may be due, in part, to a loss of thehomeostatic controls under which the normal immune system operates.Similarly, following a bone-marrow or an organ transplantation,lymphocytes recognize the foreign tissue antigens and begin to produceimmune mediators which lead to graft rejection or graft-vs-hostrejection.

One end result of an autoimmune or a rejection process is tissuedestruction caused by inflammatory cells and the mediators they release.Anti-inflammatory agents such as NSAID's act principally by blocking theeffect or secretion of these mediators but do nothing to modify theimmunologic basis of the disease. On the other hand, cytotoxic agents,such as cyclophosphamide, act in such a nonspecific fashion in whichboth the normal and autoimmune responses are shut off. Indeed, patientstreated with such nonspecific immunosuppressive agents are as likely tosuccumb to infection as they are to their autoimmune disease.

Cyclosporin A, which was approved by the US FDA in 1983 is currently theleading drug used to prevent rejection of transplanted organs. In 1993,FK-506 (Prograf) was approved by the US FDA for the prevention ofrejection in liver transplantation. Cyclosporin A and FK-506 act byinhibiting the body's immune system from mobilizing its vast arsenal ofnatural protecting agents to reject the transplant's foreign protein. In1994, Cyclosporin A was approved by the US FDA for the treatment ofsevere psoriasis and has been approved by European regulatory agenciesfor the treatment of atopic dermatitis. Though these agents areeffective in fighting transplant rejection, Cyclosporin A and FK-506 areknown to cause several undesirable side effects includingnephrotoxicity, neurotoxicity, and gastrointestinal discomfort.Therefore, a selective immunosuppressant without these side effectsstill remains to be developed. Potassium channel inhibitors as describedhere promise to be the solution to this problem, since inhibitors ofK_(v)1.3, for example, are immunosuppressive. See, Wulff et al.,“Potassium channels as therapeutic targets for autoimmune disorders,”Curr Opin Drug Discov Devel. 2003 Sep.; 6(5):640-7; Shah et al.,“Immunosuppressive effects of a K_(v)1.3 inhibitor,” Cell Immunol. 2003February; 221(2):100-6; Hanson et al., “UK-78,282, a novel piperidinecompound that potently blocks the K_(v)1.3 voltage-gated potassiumchannel and inhibits human T cell activation,” Br J. Pharmacol. 1999April; 126(8):1707-16.

Inhibitors of K_(v)1.5 and other K_(v)1.x channels stimulategastrointestinal motility. Thus, the compounds of the invention arebelieved to be useful in treating motility disorders such as refluxesophagitis. See, Frey et al., “Blocking of cloned and native delayedrectifier K channels from visceral smooth muscles by phencyclidine,”Neurogastroenterol Motil. 2000 Dec.; 12(6):509-16; Hatton et al.,“Functional and molecular expression of a voltage-dependent K(+) channel(K_(v)1.1) in interstitial cells of Caja1,” J. Physiol. 2001 Jun. 1;533(Pt 2):315-27; Vianna-Jorge et al., “Shaker-type K_(v)1 channelblockers increase the peristaltic activity of guinea-pig ileum bystimulating acetylcholine and tachykinins release by the enteric nervoussystem,” Br J. Pharmacol. 2003 January; 138(1):57-62; Koh et al.,“Contribution of delayed rectifier potassium currents to the electricalactivity of murine colonic smooth muscle,” J. Physiol. 1999 Mar. 1; 515(Pt 2):475-87.

Inhibitors of K_(v)1.5 relax pulmonary artery smooth muscle. Thus, thecompounds of the invention are believed to be useful in treatinghypertension and otherwise improving vascular health. See, Davies etal., “K_(v) channel subunit expression in rat pulmonary arteries,” Lung.2001; 179(3):147-61. Epub 2002 Feb. 4; Pozeg et al., “In vivo genetransfer of the O₂-sensitive potassium channel K_(v)1.5 reducespulmonary hypertension and restores hypoxic pulmonary vasoconstrictionin chronically hypoxic rats,” Circulation. 2003 Apr. 22;107(15):2037-44. Epub 2003 Apr. 14.

Inhibitors of K_(v)1.3 increase insulin sensitivity. Hence, thecompounds of the invention are believed to be useful in treatingdiabetes. See, Xu et al., “The voltage-gated potassium channel K_(v)1.3regulates peripheral insulin sensitivity,” Proc. Natl. Acad. Sci. U.S.A.2004 Mar. 2; 101(9):3112-7. Epub 2004 Feb. 23 (epublished 2004 Feb. 23);MacDonald et al., “Members of the K_(v)1 and K_(v)2 voltage-dependentK(+) channel families regulate insulin secretion,” Mol. Endocrinol. 2001Aug.; 15(8):1423-35; MacDonald et al., “Voltage-dependent K(+) channelsin pancreatic beta cells: role, regulation and potential as therapeutictargets,” Diabetologia. 2003 August; 46(8):1046-62. Epub 2003 Jun. 27.

Stimulation of K_(v)1.1 is believed to reduce seizure activity byhyperpolarizing neurons. Thus, the compounds of the invention arebelieved to be useful in treating seizures, including seizuresassociated with epilepsy and other neurological diseases. See, Rho etal., “Developmental seizure susceptibility of kv1.1 potassium channelknockout mice,” Dev Neurosci. 1999 Nov.; 21(3-5):320-7; Coleman et al.,“Subunit composition of K_(v)1 channels in human CNS,” J. Neurochem.1999 August; 73(2):849-58; Lopantsev et al., “Hyperexcitability of CA3pyramidal cells in mice lacking the potassium channel subunit K_(v)1.1,”Epilepsia. 2003 December; 44(12):1506-12; Wickenden, “Potassium channelsas anti-epileptic drug targets,” Neuropharmacology. 2002 December;43(7): 1055-60.

Inhibition of K_(v)1.x channels improves cognition in animal models.Thus, the compounds of the invention are believed to be useful inimproving cognition and/or treating cognitive disorders. See, Cochran etal., “Regionally selective alterations in local cerebral glucoseutilization evoked by charybdotoxin, a blocker of centralvoltage-activated K+-channels,” Eur J. Neurosci. 2001 Nov.;14(9):1455-63; Kourrich et al., “Kaliotoxin, a K_(v)1.1 and K_(v)1.3channel blocker, improves associative learning in rats,” Behav BrainRes. 2001 Apr. 8; 120(1):35-46.

SUMMARY OF THE INVENTION

In accordance with the present invention, acyclic compounds and relatedcompounds are provided that have the general structure of formula I:

wherein R¹, R², R³, R⁴ and R⁵ are defined below.

By use of a respective effective amount of at least one compounddescribed herein, provided are methods of treating (includingameliorating) or preventing arrhythmias, atrial fibrillation, atrialflutter, supraventricular arrhythmias, gastrointestinal disorders (suchas reflux esauphagitis or a motility disorder), inflammatory orimmunological disease (such as chronic obstructive pulmonary disease),diabetes, cognitive disorders, migraine, epilepsy, hypertension, ortreating I_(Kur)-associated conditions, or controlling heart rate.

Also provided are pharmaceutical compositions comprising atherapeutically effective amount of at least one compound describedherein and a pharmaceutically acceptable vehicle or carrier thereof.Such compositions can further comprise one or more other agent(s). Forexample, at least one other anti-arrhythmic agent (such as sotalol,dofetilide, diltiazem or Verapamil), or at least one calcium channelblocker, or at least one anti-platelet agent (such as clopidogrel,cangrelor, ticlopidine, CS-747, ifetroban and aspirin), or at least oneanti-hypertensive agent (such as a beta adrenergic blocker, ACEinhibitor (e.g., captopril, zofenopril, fosinopril, enalapril,ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril, orlisinopril), A II antagonist, ET antagonist, Dual ET/A II antagonist, orvasopepsidase inhibitor (e.g., omapatrilat or gemopatrilat)), or atleast one anti thrombotic/anti thrombolytic agent (such as tPA,recombinant tPA, TNK, nPA, factor VIIa inhibitors, factor Xa inhibitors(such as razaxaban), factor XIa inhibitors or thrombin inhibitors), orat least one anti coagulant (such as warfarin or a heparin), or at leastone HMG-CoA reductase inhibitor (pravastatin, lovastatin, atorvastatin,simvastatin, NK-104 or ZD-4522), or at least one anti diabetic agent(such as a biguanide or a biguanide/glyburide combination), or at leastone thyroid mimetic, or at least one mineralocorticoid receptorantagonist (such as spironolactone or eplerinone), or at least onecardiac glycoside (such as digitalis or ouabain).

DEFINITIONS

The terms “alk” or “alkyl” refer to straight or branched chainhydrocarbon groups having 1 to 12 carbon atoms, or 1 to 8 carbon atoms,such as methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl,pentyl, hexyl, heptyl, octyl, or any subset of the foregoing. The term“substituted alkyl” refers to alkyl groups substituted with one or moregroups (such as by groups described above in the definition of R¹⁰),such as selected from aryl, substituted aryl, heterocyclo, substitutedheterocyclo, carbocyclo, substituted carbocyclo, halo, hydroxy, alkoxy(optionally substituted), aryloxy (optionally substituted), alkylester(optionally substituted), arylester (optionally substituted), alkanoyl(optionally substituted), aryol (optionally substituted), cyano, nitro,amino, substituted amino, amido, lactam, urea, urethane and sulfonyl, orany subset of the foregoing.

The term “alkenyl” refers to straight or branched chain hydrocarbongroups having 2 to 12 carbon atoms, or 2 to 4 carbon atoms, and at leastone double carbon to carbon bond (either cis or trans), such as ethenyl.The term “substituted alkenyl” refers to alkenyl groups substituted withone or more groups (such as by groups described above in the definitionof R¹⁰), such as selected from aryl, substituted aryl, heterocyclo,substituted heterocyclo, carbocyclo, substituted carbocyclo, halo,hydroxy, alkoxy (optionally substituted), aryloxy (optionallysubstituted), alkylester (optionally substituted), arylester (optionallysubstituted), alkanoyl (optionally substituted), aryol (optionallysubstituted), cyano, nitro, amino, substituted amino, amido, lactam,urea, urethane and sulfonyl, or any subset of the foregoing.

The term “alkynyl” refers to straight or branched chain hydrocarbongroups having 2 to 12 carbon atoms, or 2 to 4 carbon atoms, and at leastone triple carbon to carbon bond, such as ethynyl. The term “substitutedalkynyl” refers to alkynyl groups substituted with one or more groups(such as by groups described above in the definition of R¹⁰), such asselected from aryl, substituted aryl, heterocyclo, substitutedheterocyclo, carbocyclo, substituted carbocyclo, halo, hydroxy, alkoxy(optionally substituted), aryloxy (optionally substituted), alkylester(optionally substituted), arylester (optionally substituted), alkanoyl(optionally substituted), aryol (optionally substituted), cyano, nitro,amino, substituted amino, amido, lactam, urea, urethane and sulfonyl, orany subset of the foregoing.

The term “aryl” refers to aromatic homocyclic (i.e., hydrocarbon) mono-,bi- or tricyclic ring-containing groups such as having 6 to 12 memberssuch as phenyl, naphthyl and biphenyl. Phenyl is an example of an arylgroup. The term “substituted aryl” refers to aryl groups substitutedwith one or more groups (such as by groups described above in thedefinition of R¹⁰), such as selected from alkyl, substituted alkyl,alkenyl (optionally substituted), aryl (optionally substituted),heterocyclo (optionally substituted), halo, hydroxy, alkoxy (optionallysubstituted), aryloxy (optionally substituted), alkanoyl (optionallysubstituted), aroyl, (optionally substituted), alkylester (optionallysubstituted), arylester (optionally substituted), cyano, nitro, amino,substituted amino, amido, lactam, urea, urethane and sulfonyl, or anysubset of the foregoing, where optionally one or more pair ofsubstituents together with the atoms to which they are bonded form a 3to 7 member ring.

The term “cycloalkyl” refers to mono-, bi- or tri homocyclic ring groupsof 3 to 15 carbon atoms which are, respectively, fully saturated andpartially unsaturated. The rings of multi-ring cycloalkyl groups may beeither fused, bridged and/or joined through one or more spiro unions.The term “substituted cycloalkyl” refers to a cycloalkyl groupsubstituted with one or more groups (such as by groups described abovein the definition of R¹⁰), such as selected from aryl, substituted aryl,heterocyclo, substituted heterocyclo, carbocyclo, substitutedcarbocyclo, halo, hydroxy, alkoxy (optionally substituted), aryloxy(optionally substituted), alkylester (optionally substituted), arylester(optionally substituted), alkanoyl (optionally substituted), aryol(optionally substituted), cyano, nitro, amino, substituted amino, amido,lactam, urea, urethane and sulfonyl, or any subset of the foregoing.

The terms “halogen” and “halo” refer to fluorine, chlorine, bromine andiodine.

The terms “heterocycle”, “heterocyclic”, “heterocyclic group” or“heterocyclo” refer to fully saturated or partially or completelyunsaturated, including aromatic (“heteroaryl”) or nonaromatic cyclicgroups (for example, 3 to 13 ring member monocyclic, 7 to 17 ring memberbicyclic, or 10 to 20 ring member tricyclic ring systems, such as, incertain embodiments, a monocyclic or bicyclic ring containing a total of3 to 10 ring atoms) which have at least one heteroatom in at least onecarbon atom-containing ring. Each ring of the heterocyclic groupcontaining a heteroatom may have 1, 2, 3 or 4 heteroatoms selected fromnitrogen atoms, oxygen atoms and/or sulfur atoms, where the nitrogen andsulfur heteroatoms may optionally be oxidized and the nitrogenheteroatoms may optionally be quaternized. The heterocyclic group may beattached at any heteroatom or carbon atom of the ring or ring system.The rings of multi-ring heterocycles may be either fused, bridged and/orjoined through one or more spiro unions.

Exemplary monocyclic heterocyclic groups include azetidinyl,pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl, imidazolyl,imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl, isoxazolinyl,isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl, isothiazolyl,isothiazolidinyl, furyl, tetrahydrofuryl, thienyl, oxadiazolyl,piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl,2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, 4-piperidonyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, tetrahydropyranyl,tetrazoyl, triazolyl, morpholinyl, thiamorpholinyl, thiamorpholinylsulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane andtetrahydro-1,1-dioxothienyl,

and the like.

Exemplary bicyclic heterocyclic groups include indolyl, benzothiazolyl,benzoxazolyl, benzothienyl, quinuclidinyl, quinolinyl,tetra-hydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl,indolizinyl, benzofuryl, benzofuranyl, dihydrobenzofuranyl, chromonyl,coumarinyl, benzodioxolyl, dihydrobenzodioxolyl, benzodioxinyl,cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (suchas furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl] or furo[2,3-b]pyridinyl),dihydroisoindolyl, dihydroquinazolinyl (such as3,4-dihydro-4-oxo-quinazolinyl), tetrahydroquinolinyl, azabicycloalkyls(such as 6-azabicyclo[3.2.1]octane), azaspiroalkyls (such as 1,4dioxa-8-azaspiro[4.5]decane), imidazopyridinyl (such asimidazo[1,5-a]pyridin-3-yl), triazolopyridinyl (such as1,2,4-triazolo[4,3-a]pyridin-3-yl), and hexahydroimidazopyridinyl (suchas 1,5,6,7,8,8a-hexahydroimidazo[1,5-a]pyridin-3-yl),

and the like.

Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl,phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl and the like.

The terms “substituted heterocycle”, “substituted heterocyclic”,“substituted heterocyclic group” and “substituted heterocyclo” refer toheterocycle, heterocyclic and heterocyclo groups substituted with one ormore groups (such as by groups described above in the definition ofR¹⁰), such as selected from alkyl, substituted alkyl, alkenyl, oxo,aryl, substituted aryl, heterocyclo, substituted heterocyclo, carbocyclo(optionally substituted), halo, hydroxy, alkoxy (optionallysubstituted), aryloxy (optionally substituted), alkanoyl (optionallysubstituted), aroyl (optionally substituted), alkylester (optionallysubstituted), arylester (optionally substituted), cyano, nitro, amido,amino, substituted amino, lactam, urea, urethane, sulfonyl, or anysubset of the foregoing, where optionally one or more pair ofsubstituents together with the atoms to which they are bonded form a 3to 7 member ring.

The term “alkanoyl” refers to alkyl group (which may be optionallysubstituted as described above) linked to a carbonyl group (i.e.—C(O)-alkyl). Similarly, the term “aroyl” refers to an aryl group (whichmay be optionally substituted as described above) linked to a carbonylgroup (i.e., —C(O)-aryl).

Throughout the specification, groups and substituents thereof may bechosen to provide stable moieties and compounds.

The compounds of formula I form salts or solvates which are also withinthe scope of this invention. Reference to a compound of the formula Iherein is understood to include reference to salts thereof, unlessotherwise indicated. The term “salt(s)”, as employed herein, denotesacidic and/or basic salts formed with inorganic and/or organic acids andbases. In addition, when a compound of formula I contains both a basicmoiety and an acidic moiety, zwitterions (“inner salts”) may be formedand are included within the term “salt(s)” as used herein.Pharmaceutically acceptable (i.e., non-toxic, physiologicallyacceptable) salts are preferred, although other salts are also useful,e.g., in isolation or purification steps which may be employed duringpreparation. Salts of the compounds of the formula I may be formed, forexample, by reacting a compound I with an amount of acid or base, suchas an equivalent amount, in a medium such as one in which the saltprecipitates or in an aqueous medium followed by lyophilization.

The compounds of formula I which contain a basic moiety may form saltswith a variety of organic and inorganic acids. Exemplary acid additionsalts include acetates (such as those formed with acetic acid ortrihaloacetic acid, for example, trifluoroacetic acid), adipates,alginates, ascorbates, aspartates, benzoates, benzenesulfonates,bisulfates, borates, butyrates, citrates, camphorates,camphorsulfonates, cyclopentanepropionates, digluconates,dodecylsulfates, ethanesulfonates, fumarates, glucoheptanoates,glycerophosphates, hemisulfates, heptanoates, hexanoates, hydrochlorides(formed with hydrochloric acid), hydrobromides (formed with hydrogenbromide), hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates(formed with maleic acid), methanesulfonates (formed withmethanesulfonic acid), 2-naphthalenesulfonates, nicotinates, nitrates,oxalates, pectinates, persulfates, 3-phenylpropionates, phosphates,picrates, pivalates, propionates, salicylates, succinates, sulfates(such as those formed with sulfuric acid), sulfonates (such as thosementioned herein), tartrates, thiocyanates, toluenesulfonates such astosylates, undecanoates, and the like.

The compounds of formula I which contain an acidic moiety may form saltswith a variety of organic and inorganic bases. Exemplary basic saltsinclude ammonium salts, alkali metal salts such as sodium, lithium, andpotassium salts, alkaline earth metal salts such as calcium andmagnesium salts, salts with organic bases (for example, organic amines)such as benzathines, dicyclohexylamines, hydrabamines (formed withN,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamines,N-methyl-D-glucamides, t-butyl amines, and salts with amino acids suchas arginine, lysine and the like.

Basic nitrogen-containing groups may be quaternized with agents such aslower alkyl halides (e.g. methyl, ethyl, propyl, and butyl chlorides,bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl,dibutyl, and diamyl sulfates), long chain halides (e.g. decyl, lauryl,myristyl and stearyl chlorides, bromides and iodides), aralkyl halides(e.g. benzyl and phenethyl bromides), and others.

Any compound that can be converted in vivo to provide the bioactiveagent (i.e., the compound of formula I) is a prodrug within the scopeand spirit of the invention.

The term “prodrugs” as employed herein includes esters and carbonatesformed by reacting one or more hydroxyls of compounds of formula I withalkyl, alkoxy, or aryl substituted acylating agents employing proceduresknown to those skilled in the art to generate acetates, pivalates,methylcarbonates, benzoates, and the like.

Various forms of prodrugs are well known in the art and are describedin:

a) The Practice of Medicinal Chemistry, Camille G. Wermuth et al., Ch 31(Academic Press, 1996);

b) Design of Prodrugs, edited by H. Bundgaard (Elsevier, 1985);

c) A Textbook of Drug Design and Development, P. Krogsgaard-Larson andH. Bundgaard, eds. Ch 5, pgs 113-191 (Harwood Academic Publishers,1991); and

d) Hydrolysis in Drug and Prodrug Metabolism, Bernard Testa and JoachimM. Mayer, (Wiley-VCH, 2003).

Said references are incorporated herein by reference.

In addition, compounds of the formula I are, subsequent to theirpreparation, preferably isolated and purified to obtain a compositioncontaining an amount by weight equal to or greater than 99% formula Icompound (“substantially pure” compound I), which is then used orformulated as described herein. Such “substantially pure” compounds ofthe formula I are also contemplated herein as part of the presentinvention.

To the extent that compounds of the formula I, and salts thereof, mayexist in their tautomeric form, all such tautomeric forms arecontemplated herein as part of the present invention.

All stereoisomers of the present compounds, such as those which mayexist due to asymmetric carbons on the various substituents, includingenantiomeric forms (which may exist even in the absence of asymmetriccarbons) and diastereomeric forms, are contemplated within the scope ofthis invention. Individual stereoisomers of the compounds of theinvention may, for example, be substantially free of other isomers, ormay be admixed, for example, as racemates or with all other, or otherselected, stereoisomers.

The terms “including”, “such as”, “for example” and the like areintended to refer to exemplary embodiments and not to limit the scope ofthe present invention.

DETAILED DESCRIPTION OF THE INVENTION

It will be understood that any given exemplary embodiment can becombined with one or more additional exemplary embodiments.

In accordance with the present invention, compounds of formula I areprovided

or stereoisomers or pharmaceutically acceptable salts or prodrugsthereof, wherein:R¹ is an aryl or heterocyclic ring, which may be optionally substitutedwith one or more R¹⁰'s;R² and R³ are independently:

(a) halo,

(b) (C₁-C₆)-alkoxy optionally substituted with one or more R¹¹'s,

(c) (C₁-C₄)-perfluoroalkyl,

(d) (C₁-C₆)-alkyl-S(O)_(n)—,

(e) aryl-(CH₂)_(r)—S(O)_(n)—,

(f) cyano,

(g) —CO₂H,

(h) —CO(C₁-C₆)-alkyl,

(i) —CO₂(C₁-C₆)-alkyl,

(j) —CONR⁸R⁹,

(k) —O(CO)NR⁸R⁹,

(l) —NR⁸(CO)NR⁸R⁹,

(m) —NR⁸R⁹,

(n) hydrogen,

(o) C₁-C₁₀-alkyl optionally substituted with one or more R¹¹'s,

(p) (C₂-C₁₀)-alkenyl optionally substituted with one or more R¹¹'s,

(q) (C₂-C₁₀)-alkynyl optionally substituted with one or more R¹¹'s,

(r) aryl optionally substituted with one or more R¹¹'s,

(s) heterocyclyl optionally substituted with one or more R¹¹'s, or

(t) —NR⁸(CO)OR²¹,

provided that both R² and R³ are not simultaneously hydrogen;

R⁴ is:

-   -   (a) hydrogen,    -   (b) C₁-C₁₀-alkyl,    -   (c) —CO(C₁-C₆)-alkyl,    -   (d) —COaryl,    -   (e) —COheterocyclyl,    -   (f) —CO₂(C₁-C₆)-alkyl,    -   (g) —CO₂aryl,    -   (h) —CO₂heterocyclyl,    -   (i) —CONR⁸R⁹,    -   (j) —S(O)_(n)-alkyl,    -   (k) —S(O)_(n)-aryl,    -   (l) —S(O)_(n)-heterocyclyl, or    -   (m) —S(O)_(n)—NR⁸R⁹;        R⁵ is        wherein the dashed line(s) represent an optional double bond;        T is O, S, C═O, N, NR¹⁹ or C(R²⁰)_(p);        Q, X, U, V and W are independently O, S, C═O, N, NR¹⁹ or        C(R²⁰)_(p),        provided that Q is not C(R²⁰)_(p) when X is N or NR¹⁹;        R⁸ and R⁹ are independently:

(a) hydrogen,

(b) —[(C═O)O_(r)]_(s)aryl, wherein the aryl may be optionallysubstituted with one or more R¹⁴'s,

(c) —[(C═O)O_(r)]_(s)(C₂-C₈)-alkenyl, wherein the alkenyl may beoptionally substituted with one or more R¹⁴'s,

(d) —[(C═O)O_(r)]_(s)(C₁-C₈)alkyl, wherein the alkyl may be optionallysubstituted with one or more R¹⁴'s,

(e) —S(O)_(p)(C₁-C₈)alkyl, wherein the alkyl may be optionallysubstituted with one or more R¹⁴'s,

(f) —S(O)_(p)NR¹⁶R¹⁷,

(g) —C(═NR¹⁸)(NR¹⁶R¹⁷), or

(h) heterocyclyl optionally substituted with one or more R¹⁴'s,

or R⁸ and R⁹ are taken together with the nitrogen to which both areattached to form a 3- to 8-membered ring, which may optionally contain1-4 heteroatoms selected from N, O, and S and be optionally substitutedwith one or more R¹⁴'s;

R¹⁰ is:

(a) halo,

(b) —OH,

(c) —O[(C═O)O_(r)]_(s)(C₁-C₆)-alkyl,

(d) —O[(C═O)O_(r)]_(s)(C₂-C₆)-alkenyl,

(e) —O[(C═O)O_(r)]_(s)aryl,

(f) —O[(C═O)O_(r)]_(s)heteroaryl,

(g) (C₁-C₆)-alkyl-S(O)_(n)—,

(h) aryl-(C₁-C₆)alkyloxy-,

(i) cyano,

(j) nitro,

(k) —NR⁸R⁹,

(l) —O(CO)NR⁸R⁹,

(m) —CHO,

(n) —COOH,

(o) —CO(C₁-C₆)-alkyl,

(p) —CO₂(C₁-C₆)-alkyl,

(q) —CONR⁸R⁹,

(r) aryl, which may optionally be substituted with one or moresubstituents selected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyl,    -   4) (C₁-C₄)-perfluoroalkyl,    -   5) (C₂-C₆)-alkenyl,    -   6) (C₂-C₆)-alkynyl,    -   7) (C₁-C₆)-alkyloxy,    -   8) (C₁-C₆)-alkyl-S(O)_(n)—,    -   9) cyano,    -   10) —COOH,    -   11) —CO(C₁-C₆)-alkyl,    -   12) —CO₂(C₁-C₆)-alkyl,    -   13) —CONR⁸R⁹,    -   14) —NR⁸R⁹,    -   15) —O(C═O)—(C₁-C₆)-alkyl, and    -   16) —O(C═O)NR⁸R⁹,

(s) heteroaryl optionally substituted with one or more substituentsselected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyl,    -   4) (C₁-C₄)-perfluoroalkyl,    -   5) (C₂-C₆)-alkenyl,    -   6) (C₂-C₆)-alkynyl,    -   7) (C₁-C₆)-alkyloxy,    -   8) (C₁-C₆)-alkyl-S(O)_(n)—,    -   9) cyano,    -   10) —COOH,    -   11) —CO(C₁-C₆)-alkyl,    -   12) —CO₂(C₁-C₆)-alkyl,    -   13) —CONR⁸R⁹,    -   14) —NR⁸R⁹,    -   15) —O(C═O)—(C₁-C₆)-alkyl, and    -   16) —O(C═O)NR⁸R⁹,

(t) heterocyclo other than heteroaryl which is optionally substitutedwith one or more substituents selected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyl,    -   4) (C₁-C₄)-perfluoroalkyl,    -   5) (C₂-C₆)-alkenyl,    -   6) (C₂-C₆)-alkynyl,    -   7) (C₁-C₆)-alkyloxy,    -   8) (C₁-C₆)-alkyl-S(O)_(n)—,    -   9) cyano,    -   10) —COOH,    -   11) —CO(C₁-C₆)-alkyl,    -   12) —CO₂(C₁-C₆)-alkyl,    -   13) —CONR⁸R⁹,    -   14) —NR⁸R⁹,    -   15) —O(C═O)—(C₁-C₆)-alkyl, and    -   16) —O(C═O)NR⁸R⁹,

(u) benzyl-S(O)_(n)—,

(v) (C₂-C₁₀)-alkenyl, which may optionally be substituted with one ormore substituents selected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyloxy,    -   4) (C₁-C₆)-alkyl-S(O)_(n)—,    -   5) cyano,    -   6) —COOH,    -   7) —CO(C₁-C₆)-alkyl,    -   8) —CO₂(C₁-C₆)-alkyl,    -   9) —CONR⁸R⁹,    -   10) —NR⁸R⁹,    -   11) —O(C═O)—(C₁-C₆)-alkyl, and    -   12) —O(C═O)NR⁸R⁹,

(w) (C₂-C₁₀)-alkynyl wherein alkynyl is optionally substituted with oneor more substituents selected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyloxy,    -   4) (C₁-C₆)-alkyl-S(O)_(n)—,    -   5) cyano,    -   6) —COOH,    -   7) —CO(C₁-C₆)-alkyl,    -   8) —CO₂(C₁-C₆)-alkyl,    -   9) —CONR⁸R⁹,    -   10) —NR⁸R⁹,    -   11) —O(C═O)—(C₁-C₆)-alkyl, and    -   12) —O(C═O)NR⁸R⁹,

(x) —(C₁-C₁₀)-alkyl, which may optionally be substituted with one ormore substituents selected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyloxy,    -   4) (C₁-C₆)-alkyl-S(O)_(n)—,    -   5) benzyl-S(O)_(n)—,    -   6) cyano,    -   7) —COOH,    -   8) —CO(C₁-C₆)-alkyl,    -   9) —CO₂(C₁-C₆)-alkyl,    -   10) —CONR⁸R⁹,    -   11) —NR⁸R⁹,    -   12) —(C═O)—(C₁-C₆)-alkyl, and    -   13) —(C═O)NR⁸R⁹;        R¹¹ is:

(a) halo,

(b) —OH,

(c) —O[(C═O)O_(r)]_(s)(C₁-C₆)-alkyl,

(d) —O[(C═O)O_(r)]_(s)(C₂-C₆)-alkenyl,

(e) —O[(C═O)O_(r)]_(s)aryl,

(f) —O[(C═O)O_(r)]_(s)heteroaryl,

(g) (C₁-C₆)-alkyl-S(O)_(n)—,

(h) aryl-(C₁-C₆)alkyloxy-,

(i) cyano,

(j) —NR⁸R⁹,

(k) —O(CO)NR⁸R⁹,

(l) —COOH,

(m) —CO(C₁-C₆)-alkyl,

(n) —CO₂(C₁-C₆)-alkyl,

(o) —CONR⁸R⁹,

(p) aryl, which may optionally be substituted with one or moresubstituents selected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyl,    -   4) aryl-(C₁-C₆)alkyloxy-,    -   5) (C₁-C₄)-perfluoroalkyl,    -   6) (C₂-C₆)-alkenyl,    -   7) (C₂-C₆)-alkynyl,    -   8) (C₁-C₆)-alkyloxy,    -   9) (C₁-C₆)-alkyl-S(O)_(n)—,    -   10) cyano,    -   11) —COOH,    -   12) —CO(C₁-C₆)-alkyl,    -   13) —CO₂(C₁-C₆)-alkyl,    -   14) —CONR⁸R⁹,    -   15) —NR⁸R⁹,    -   16) —O(C═O)—(C₁-C₆)-alkyl, and    -   17) —O(C═O)NR⁸R⁹,

(q) heteroaryl optionally substituted with one or more substituentsselected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyl,    -   4) aryl-(C₁-C₆)alkyloxy-,    -   5) (C₁-C₄)-perfluoroalkyl,    -   6) (C₂-C₆)-alkenyl,    -   7) (C₂-C₆)-alkynyl,    -   8) (C₁-C₆)-alkyloxy,    -   9) (C₁-C₆)-alkyl-S(O)_(n)—,    -   10) cyano,    -   11) —COOH,    -   12) —CO(C₁-C₆)-alkyl,    -   13) —CO₂(C₁-C₆)-alkyl,    -   14) —CONR⁸R⁹,    -   15) —NR⁸R⁹,    -   16) —O(C═O)—(C₁-C₆)-alkyl, and    -   17) —O(C═O)NR⁸R⁹,

(r) heterocyclo other than heteroaryl which is optionally substitutedwith one or more substituents selected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyl,    -   4) aryl-(C₁-C₆)alkyloxy-,    -   5) (C₁-C₄)-perfluoroalkyl,    -   6) (C₂-C₆)-alkenyl,    -   7) (C₂-C₆)-alkynyl,    -   8) (C₁-C₆)-alkyloxy,    -   9) (C₁-C₆)-alkyl-S(O)_(n)—,    -   10) cyano,    -   11) —COOH,    -   12) —CO(C₁-C₆)-alkyl,    -   13) —CO₂(C₁-C₆)-alkyl,    -   14) —CONR⁸R⁹,    -   15) —NR⁸R⁹,    -   16) —O(C═O)—(C₁-C₆)-alkyl, and    -   17) —O(C═O)NR⁸R⁹,

(s) —(C₂-C₁₀)-alkenyl, which may optionally be substituted with one ormore substituents selected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyloxy    -   4) (C₁-C₆)-alkyl-S(O)_(n)—,    -   5) phenyl-(C₁-C₆)-alkyloxy-,    -   6) cyano,    -   7) —CHO,    -   8) —COOH,    -   9) —CO(C₁-C₆)-alkyl,    -   10) —CO₂(C₁-C₆)-alkyl,    -   11) —CONR⁸R⁹,    -   12) —NR⁸R⁹,    -   13) aryl,    -   14) heteroaryl as defined above,    -   15) heterocyclo other than heteroaryl as defined above,    -   16) —O(C═O)—(C₁-C₆)-alkyl, and    -   17) —O(C═O)NR⁸R⁹,

(t) (C₂-C₁₀)-alkynyl wherein alkynyl is optionally substituted with oneor more substituents selected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyloxy,    -   4) (C₁-C₆)-alkyl-S(O)_(n)—,    -   5) phenyl-(C₁-C₆)-alkyloxy-,    -   6) cyano,    -   7) vinyl,    -   8) —CHO,    -   9) —COOH,    -   10) —CO(C₁-C₆)-alkyl,    -   11) —CO₂(C₁-C₆)-alkyl,    -   12) —CONR⁸R⁹,    -   13) —NR⁸R⁹,    -   14) aryl, wherein aryl is defined as above,    -   15) heteroaryl as defined above,    -   16) heterocyclyl other than heteroaryl as defined above,    -   17) —O(C═O)—(C₁-C₆)-alkyl, and    -   18) —O(C═O)NR⁸R⁹,

(u) —(C₁-C₁₀)-alkyl, which may optionally be substituted with one ormore substituents selected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyloxy,    -   4) (C₁-C₆)-alkyl-S(O)_(n)—,    -   5) benzyl-S(O)_(n)—,    -   6) cyano,    -   7) —COOH,    -   8) —CO(C₁-C₆)-alkyl,    -   9) —CO₂(C₁-C₆)-alkyl,    -   10) —CONR⁸R⁹,    -   11) —NR⁸R⁹,    -   12) —O(C═O)—(C₁-C₆)-alkyl, and    -   13) —O(C═O)NR⁸R⁹,

(v) —O(CH₂)_(m)-heteroaryl as defined above;

R¹² is:

(a) halo,

(b) —OH,

(c) —O[(C═O)O_(r)]_(s)(C₁-C₆)-alkyl,

(d) —O[(C═O)O_(r)]_(s)(C₂-C₆)-alkenyl,

(e) —O[(C═O)O_(r)]_(s)aryl,

(f) —O[(C═O)O_(r)]_(s)heteroaryl,

(g) (C₁-C₆)-alkyl-S(O)_(n)—,

(h) aryl-(C₁-C₆)alkyloxy-,

(i) cyano,

(j) nitro,

(k) —NR⁸R⁹,

(l) —O(CO)NR⁸R⁹,

(m) —HO,

(n) —COOH,

(o) —O(C₁-C₆)-alkyl,

(p) —CO₂(C₁-C₆)-alkyl,

(q) —CONR⁸R⁹,

(r) aryl, which may optionally be substituted with one or moresubstituents selected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyl,    -   4) (C₁-C₄)-perfluoroalkyl,    -   5) (C₂-C₆)-alkenyl,    -   6) (C₂-C₆)-alkynyl,    -   7) (C₁-C₆)-alkyloxy,    -   8) (C₁-C₆)-alkyl-S(O)_(n)—,    -   9) cyano,    -   10) —COOH,    -   11) —CO(C₁-C₆)-alkyl,    -   12) —CO₂(C₁-C₆)-alkyl,    -   13) —CONR⁸R⁹,    -   14) —NR⁸R⁹,    -   15) —O(C═O)—(C₁-C₆)-alkyl, and    -   16) —O(C═O)NR⁸R⁹,

(s) heteroaryl optionally substituted with one or more substituentsselected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyl,    -   4) (C₁-C₄)-perfluoroalkyl,    -   5) (C₂-C₆)-alkenyl,    -   6) (C₂-C₆)-alkynyl,    -   7) (C₁-C₆)-alkyloxy,    -   8) (C₁-C₆)-alkyl-S(O)_(n)—,    -   9) cyano,    -   10) —COOH,    -   11) —CO(C₁-C₆)-alkyl,    -   12) —CO₂(C₁-C₆)-alkyl,    -   13) —CONR⁸R⁹,    -   14) —NR⁸R⁹,    -   15) —O(C═O)—(C₁-C₆)-alkyl, and    -   16) —O(C═O)NR⁸R⁹,

(t) heterocyclo other than heteroaryl which is optionally substitutedwith one or more substituents selected from the group consisting of:

-   -   1) halo,    -   52) —OH,    -   3) (C₁-C₆)-alkyl,    -   4) (C₁-C₄)-perfluoroalkyl,    -   5) (C₂-C₆)-alkenyl,    -   6) (C₂-C₆)-alkynyl,    -   7) (C₁-C₆)-alkyloxy,    -   8) (C₁-C₆)-alkyl-S(O)_(n)—,    -   9) cyano,    -   10) —COOH,    -   11) —CO(C₁-C₆)-alkyl,    -   12) —CO₂(C₁-C₆)-alkyl,    -   13) —CONR⁸R⁹,    -   14) —NR⁸R⁹,    -   15) —O(C═O)—(C₁-C₆)-alkyl, and    -   16) —O(C═O)NR⁸R⁹,

(u) benzyl-S(O)_(n)—,

(v) (C₂-C₁₀)-alkenyl, which may optionally be substituted with one ormore substituents selected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyloxy,    -   4) (C₁-C₆)-alkyl-S(O)_(n)—,    -   5) cyano,    -   6) —COOH,    -   7) —CO(C₁-C₆)-alkyl,    -   8) —CO₂(C₁-C₆)-alkyl,    -   9) —CONR⁸R⁹,    -   10) —NR⁸R⁹,    -   11) —O(C═O)—(C₁-C₆)-alkyl, and    -   12) —O(C═O)NR⁸R⁹,

(w) (C₂-C₁₀)-alkynyl wherein alkynyl is optionally substituted with oneor more substituents selected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyloxy,    -   4) (C₁-C₆)-alkyl-S(O)_(n)—,    -   5) cyano,    -   6) —COOH,    -   7) —CO(C₁-C₆)-alkyl,    -   8) —CO₂(C₁-C₆)-alkyl,    -   9) —CONR⁸R⁹,    -   10) —NR⁸R⁹,    -   11) —O(C═O)—(C₁-C₆)-alkyl, and    -   12) —O(C═O)NR⁸R⁹,

(x) —(C₁-C₁₀)-alkyl, which may optionally be substituted with one ormore substituents selected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyloxy,    -   4) (C₁-C₆)-alkyl-S(O)_(n)—,    -   5) benzyl-S(O)_(n)—,    -   6) cyano,    -   7) —COOH,    -   8) —CO(C₁-C₆)-alkyl,    -   9) —CO₂(C₁-C₆)-alkyl,    -   10) —CONR⁸R⁹,    -   11) —NR⁸R⁹,    -   12) —O(C═O)—(C₁-C₆)-alkyl, and    -   13) —O(C═O)NR⁸R⁹,

(y) ═O;

R¹⁴ is:

(a) halo,

(b) —OH,

(c) —O[(C═O)O_(r)]_(s)(C₁-C₆)-alkyl,

(d) —O[(C═O)O_(r)]_(s)(C₂-C₆)-alkenyl,

(e) —O[(C═O)O_(r)]_(s)aryl,

(f) —O[(C═O)O_(r)]_(s)heteroaryl,

(g) (C₁-C₆)-alkyl-S(O)_(n)—,

(h) aryl-(C₁-C₆)alkyloxy-,

(i) cyano,

(j) nitro,

(k) —NR⁸R⁹,

(l) —O(CO)NR⁸R⁹,

(m) —CHO,

(n) —COOH,

(o) —CO(C₁-C₆)-alkyl,

(p) —CO₂(C₁-C₆)-alkyl,

(q) —CONR⁸R⁹,

(r) aryl, which may optionally be substituted with one or moresubstituents selected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyl,    -   4) (C₁-C₄)-perfluoroalkyl,    -   5) (C₂-C₆)-alkenyl,    -   6) (C₂-C₆)-alkynyl,    -   7) (C₁-C₆)-alkyloxy,    -   8) (C₁-C₆)-alkyl-S(O)_(n)—,    -   9) cyano,    -   10) —COOH,    -   11) —CO(C₁-C₆)-alkyl,    -   12) —CO₂(C₁-C₆)-alkyl,    -   13) —CONR⁸R⁹,    -   14) —NR⁸R⁹,    -   15) —O(C═O)—(C₁-C₆)-alkyl, and    -   16) —O(C═O)NR⁸R⁹,

(s) heteroaryl optionally substituted with one or more substituentsselected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyl,    -   4) (C₁-C₄)-perfluoroalkyl,    -   5) (C₂-C₆)-alkenyl,    -   6) (C₂-C₆)-alkynyl,    -   7) (C₁-C₆)-alkyloxy,    -   8) (C₁-C₆)-alkyl-S(O)_(n)—,    -   9) cyano,    -   10) —COOH,    -   11) —CO(C₁-C₆)-alkyl,    -   12) —CO₂(C₁-C₆)-alkyl,    -   13) —CONR⁸R⁹,    -   14) —NR⁸R⁹,    -   15) —O(C═O)—(C₁-C₆)-alkyl, and    -   16) —O(C═O)NR⁸R⁹,

(t) heterocyclo other than heteroaryl which is optionally substitutedwith one or more substituents selected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyl,    -   4) (C₁-C₄)-perfluoroalkyl,    -   5) (C₂-C₆)-alkenyl,    -   6) (C₂-C₆)-alkynyl,    -   7) (C₁-C₆)-alkyloxy,    -   8) (C₁-C₆)-alkyl-S(O)_(n)—,    -   9) cyano,    -   10) —COOH,    -   11) —CO(C₁-C₆)-alkyl,    -   12) —CO₂(C₁-C₆)-alkyl,    -   13) —CONR⁸R⁹,    -   14) —NR⁸R⁹,    -   15) —O(C═O)—(C₁-C₆)-alkyl, and    -   16) —O(C═O)NR⁸R⁹,

(u) benzyl-S(O)_(n)—,

(v) (C₂-C₁₀)-alkenyl, which may optionally be substituted with one ormore substituents selected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyloxy,    -   4) (C₁-C₆)-alkyl-S(O)_(n)—,    -   5) cyano,    -   6) —COOH,    -   7) —CO(C₁-C₆)-alkyl,    -   8) —CO₂(C₁-C₆)-alkyl,    -   9) —CONR⁸R⁹,    -   10) —NR⁸R⁹,    -   11) —O(C═O)—(C₁-C₆)-alkyl, and    -   12) —O(C═O)NR⁸R⁹,

(w) (C₂-C₁₀)-alkynyl wherein alkynyl is optionally substituted with oneor more substituents selected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyloxy,    -   4) (C₁-C₆)-alkyl-S(O)_(n)—,    -   5) cyano,    -   6) —COOH,    -   7) —CO(C₁-C₆)-alkyl,    -   8) —CO₂(C₁-C₆)-alkyl,    -   9) —CONR⁸R⁹,    -   10) —NR⁸R⁹,    -   11) —O(C═O)—(C₁-C₆)-alkyl, and    -   12) —O(C═O)NR⁸R⁹,

(x) —(C₁-C₁₀)-alkyl, which may optionally be substituted with one ormore substituents selected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyloxy,    -   4) (C₁-C₆)-alkyl-S(O)_(n)—,    -   5) benzyl-S(O)_(n)—,    -   6) cyano,    -   7) —COOH,    -   8) —CO(C₁-C₆)-alkyl,    -   9) —CO₂(C₁-C₆)-alkyl,    -   10) —CONR⁸R⁹,    -   11) —NR⁸R⁹,    -   12) —O(C═O)—(C₁-C₆)-alkyl, and    -   13) —O(C═O)NR⁸R⁹;        R¹⁶ and R¹⁷ are independently:

(a) aryl, which may optionally be substituted with one or moresubstituents selected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyl,    -   4) (C₁-C₄)-perfluoroalkyl,    -   5) (C₂-C₆)-alkenyl,    -   6) (C₂-C₆)-alkynyl,    -   7) (C₁-C₆)-alkyloxy,    -   8) (C₁-C₆)-alkyl-S(O)_(n)—,    -   9) cyano,    -   10) —COOH,    -   11) —CO(C₁-C₆)-alkyl,    -   12) —CO₂(C₁-C₆)-alkyl,    -   13) —CONR⁸R⁹,    -   14) —NR⁸R⁹,    -   15) —O(C═O)—(C₁-C₆)-alkyl, and    -   16) —O(C═O)NR⁸R⁹,

(b) heteroaryl optionally substituted with one or more substituentsselected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyl,    -   4) (C₁-C₄)-perfluoroalkyl,    -   5) (C₂-C₆)-alkenyl,    -   6) (C₂-C₆)-alkynyl,    -   7) (C₁-C₆)-alkyloxy,    -   8) (C₁-C₆)-alkyl-S(O)_(n)—,    -   9) cyano,    -   10) —COOH,    -   11) —CO(C₁-C₆)-alkyl,    -   12) —CO₂(C₁-C₆)-alkyl,    -   13) —CONR⁸R⁹,    -   14) —NR⁸R⁹,    -   15) —O(C═O)—(C₁-C₆)-alkyl, and    -   16) —O(C═O)NR⁸R⁹,

(c) heterocyclo other than heteroaryl which is optionally substitutedwith one or more substituents selected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyl,    -   4) (C₁-C₄)-perfluoroalkyl,    -   5) (C₂-C₆)-alkenyl,    -   6) (C₂-C₆)-alkynyl,    -   7) (C₁-C₆)-alkyloxy,    -   8) (C₁-C₆)-alkyl-S(O)_(n)—,    -   9) cyano,    -   10) —COOH,    -   11) —CO(C₁-C₆)-alkyl,    -   12) —CO₂(C₁-C₆)-alkyl,    -   13) —CONR⁸R⁹,    -   14) —NR⁸R⁹,    -   15) —O(C═O)—(C₁-C₆)-alkyl, and    -   16) —O(C═O)NR⁸R⁹,

(d) (C₂-C₁₀)-alkenyl, which may optionally be substituted with one ormore substituents selected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyloxy,    -   4) (C₁-C₆)-alkyl-S(O)_(n)—,    -   5) cyano,    -   6) —COOH,    -   7) —CO(C₁-C₆)-alkyl,    -   8) —CO₂(C₁-C₆)-alkyl,    -   9) —CONR⁸R⁹,    -   10) —NR⁸R⁹,    -   11) —O(C═O)—(C₁-C₆)-alkyl, and    -   12) —O(C═O)NR⁸R⁹,

(e) (C₂-C₁₀)-alkynyl wherein alkynyl is optionally substituted with oneor more substituents selected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyloxy,    -   4) (C₁-C₆)-alkyl-S(O)_(n)—,    -   5) cyano,    -   6) —COOH,    -   7) —CO(C₁-C₆)-alkyl,    -   8) —CO₂(C₁-C₆)-alkyl,    -   9) —CONR⁸R⁹,    -   10) —NR⁸R⁹,    -   11) —O(C═O)—(C₁-C₆)-alkyl, and    -   12) —O(C═O)NR⁸R⁹,

(f) —(C₁-C₁₀)-alkyl, which may optionally be substituted with one ormore substituents selected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyloxy,    -   4) (C₁-C₆)-alkyl-S(O)_(n)—,    -   5) benzyl-S(O)_(n)—,    -   6) cyano,    -   7) —COOH,    -   8) —CO(C₁-C₆)-alkyl,    -   9) —CO₂(C₁-C₆)-alkyl,    -   10) —CONR⁸R⁹,    -   11) —NR⁸R⁹,    -   12) —O(C═O)—(C₁-C₆)-alkyl, and    -   13) —O(C═O)NR⁸R⁹,        or R¹⁶ and R¹⁷ are taken together with the nitrogen to which        both are attached to form a 3- to 8-membered ring, which may        optionally contain 1-4 heteroatoms selected from N, O, and S and        be optionally substituted with one or more R¹⁴'s;        R¹⁸ is cyano, —COR¹⁶ or —SO₂R¹⁶;        R¹⁹ is:

(a) hydrogen,

(b) (C₁-C₆)-alkyl,

(c) —CO(C₁-C₆)-alkyl,

(d) —CO(C₁-C₆)-aryl,

(e) —CO(C₁-C₆)-heteroaryl,

(f) —CO₂(C₁-C₆)-alkyl,

(g) CO₂(C₁-C₆)-aryl,

(h) CO₂(C₁-C₆)-heteroaryl,

(i) —CONR⁸R⁹,

(j) —S(O)_(n)-alkyl,

(k) —S(O)_(n)-aryl,

(l) —S(O)_(n)-heteroaryl, or

(m) —S(O)_(n)—NR⁸R⁹;

R²⁰ is independently:

(a) hydrogen,

(b) halo,

(c) —OH,

(d) —O[(C═O)O_(r)]_(s)(C₁-C₆)-alkyl,

(e) —O[(C═O)O_(r)]_(s)(C₂-C₆)-alkenyl,

(f) —O[(C═O)O_(r)]_(s)aryl,

(g) —O[(C═O)O_(r)]_(s)heteroaryl,

(h) (C₁-C₆)-alkyl-S(O)_(n)—,

(i) aryl-(C₁-C₆)alkyloxy-,

(j) cyano,

(k) nitro,

(l) —NR⁸R⁹,

(m) —O(CO)NR⁸R⁹,

(n) —CHO,

(o) COOH,

(p) —CO(C₁-C₆)-alkyl,

(q) —CO₂(C₁-C₆)-alkyl,

(r) —CONR⁸R⁹,

(s) aryl, which may optionally be substituted with one or moresubstituents selected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyl,    -   4) (C₁-C₄)-perfluoroalkyl,    -   5) (C₂-C₆)-alkenyl,    -   6) (C₂-C₆)-alkynyl,    -   7) (C₁-C₆)-alkyloxy,    -   8) (C₁-C₆)-alkyl-S(O)_(n)—,    -   9) cyano,    -   10) —COOH,    -   11) —CO(C₁-C₆)-alkyl,    -   12) —CO₂(C₁-C₆)-alkyl,    -   13) —CONR⁸R⁹,    -   14) —NR⁸R⁹,    -   15) —O(C═O)—(C₁-C₆)-alkyl, and    -   16) —O(C═O)NR⁸R⁹,

(t) heteroaryl optionally substituted with one or more substituentsselected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyl,    -   4) (C₁-C₄)-perfluoroalkyl,    -   5) (C₂-C₆)-alkenyl,    -   6) (C₂-C₆)-alkynyl,    -   7) (C₁-C₆)-alkyloxy,    -   8) (C₁-C₆)-alkyl-S(O)_(n)—,    -   9) cyano,    -   10) —COOH,    -   11) —CO(C₁-C₆)-alkyl,    -   12) —CO₂(C₁-C₆)-alkyl,    -   13) —CONR⁸R⁹,    -   14) —NR⁸R⁹,    -   15) —O(C═O)—(C₁-C₆)-alkyl, and    -   16) —O(C═O)NR⁸R⁹,

(u) heterocyclo other than heteroaryl which is optionally substitutedwith one or more substituents selected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyl,    -   4) (C₁-C₄)-perfluoroalkyl,    -   5) (C₂-C₆)-alkenyl,    -   6) (C₂-C₆)-alkynyl,    -   7) (C₁-C₆)-alkyloxy,    -   8) (C₁-C₆)-alkyl-S(O)_(n)—,    -   9) cyano,    -   10) —COOH,    -   11) —CO(C₁-C₆)-alkyl,    -   12) —CO₂(C₁-C₆)-alkyl,    -   13) —CONR⁸R⁹,    -   14) —NR⁸R⁹,    -   15) —O(C═O)—(C₁-C₆)-alkyl, and    -   16) —O(C═O)NR⁸R⁹,

(v) benzyl-S(O)_(n)—,

(w) (C₂-C₁₀)-alkenyl, which may optionally be substituted with one ormore substituents selected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyloxy,    -   4) (C₁-C₆)-alkyl-S(O)_(n)—,    -   5) cyano,    -   6) —COOH,    -   7) —CO(C₁-C₆)-alkyl,    -   8) —CO₂(C₁-C₆)-alkyl,    -   9) —CONR⁸R⁹,    -   10) —NR⁸R⁹,    -   11) —O(C═O)—(C₁-C₆)-alkyl, and    -   12) —O(C═O)NR⁸R⁹,

(x) (C₂-C₁₀)-alkynyl wherein alkynyl is optionally substituted with oneor more substituents selected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyloxy,    -   4) (C₁-C₆)-alkyl-S(O)_(n)—,    -   5) cyano,    -   6) —COOH,    -   7) —CO(C₁-C₆)-alkyl,    -   8) —CO₂(C₁-C₆)-alkyl,    -   9) —CONR⁸R⁹,    -   10) —NR⁸R⁹,

11) —O(C═O)—(C₁-C₆)-alkyl, and

-   -   12) —O(C═O)NR⁸R⁹,

(y) —(C₁-C₁₀)-alkyl, which may optionally be substituted with one ormore substituents selected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyloxy,    -   4) (C₁-C₆)-alkyl-S(O)_(n)—,    -   5) benzyl-S(O)_(n)—,    -   6) cyano,    -   7) —COOH,    -   8) —CO(C₁-C₆)-alkyl,    -   9) —CO₂(C₁-C₆)-alkyl,    -   10) —CONR⁸R⁹,    -   11) —NR⁸R⁹,    -   12) —O(C═O)—(C₁-C₆)-alkyl, and    -   13) —O(C═O)NR⁸R⁹;        R²¹ is:

(a) C₁-C₁₀-alkyl optionally substituted with one or more R¹¹'s,

(b) C₃-C₈-cycloalkyl optionally substituted with one or more R¹¹'s,

(c) aryl optionally substituted with one or more R¹¹'s, or

(d) heterocyclyl optionally substituted with one or more R¹¹'s;

m is 1 to 5;

n is 0 to 3;

p is 1 or 2;

r is 0 to 5; and

s is 0 to 4.

In one embodiment, compounds of formula I are provided wherein R¹ is amonocylic aryl ring, for example, phenyl, which may be optionallysubstituted with one or more R¹⁰'s.

In another embodiments of the invention, compounds of formula I areprovided wherein R¹ is a monocylic heterocyclic ring, for example,pyridinyl, which may be optionally substituted with one or more R¹⁰'s.

In yet another embodiment, compounds of formula I are provided whereinR⁵ is

In still yet another embodiment, compounds of formula I are providedwherein R⁵ is

In one embodiment, compounds of formula I are provided wherein T is O,S, C═O, NR¹⁹ or CR²⁰; and U, V, and W are C(R²⁰)_(p). In anotherembodiment, T is O, S, C═O or NR¹⁹.

In yet another embodiment, compounds of formula I are provided whereinR⁵ is

and both Q and X are not C═O.

In still yet another embodiment, compounds of formula I are providedwherein U, V, and W are (CR²⁰)_(p). In one embodiment, Q is C═O and X isO, N or NR¹⁹. In another embodiment, Q is O or NR¹⁹ and X is C═O.

In one embodiment, compounds of formula I are provide wherein:

R¹ is an aryl or heterocyclic ring, which may be optionally substitutedwith one or more R¹⁰'s;

R² and R³ are independently:

(a) halo,

(b) (C₁-C₆)-alkoxy optionally substituted with one or more R¹¹'s,

(c) (C₁-C₄)-perfluoroalkyl,

(d) —CO(C₁-C₆)-alkyl,

(e) —CO₂(C₁-C₆)-alkyl,

(f) —CONR⁸R⁹,

(g) —O(CO)NR⁸R⁹,

(h) —NR⁸(CO)NR⁸R⁹,

(i) —NR⁸R⁹,

(j) hydrogen,

(k) C₁-C₁₀-alkyl optionally substituted with one or more R¹¹'s,

(l) aryl optionally substituted with one or more R¹¹'s,

(m) heterocyclyl optionally substituted with one or more R¹¹'s, or

(n) —NR⁸(CO)OR²¹,

provided that both R² and R³ are not simultaneously hydrogen;

R⁴ is:

(a) hydrogen,

(b) C₁-C₁₀-alkyl,

(c) —CO(C₁-C₆)-alkyl,

(d) —COaryl,

(e) —COheterocyclyl,

(f) —CO₂(C₁-C₆)-alkyl,

(g) CO₂aryl, or

(h) CO₂heterocyclyl;R⁵ is

Q is a O, C═O, N, NR¹⁹ or C(R²⁰)_(p);T is O, S, C═O, N, NR¹⁹ or C(R²⁰)_(p);X, U, V and W are independently O, C═O or C(R²⁰)_(p);R⁸ and R⁹ are independently:

(a) hydrogen,

(b) —[(C═O)O_(r)]_(s)aryl, wherein the aryl may be optionallysubstituted with one or more R¹⁴'s,

(c) —[(C═O)O_(r)]_(s)(C₂-C₈)-alkenyl, wherein the alkenyl may beoptionally substituted with one or more R¹⁴'s,

(d) —[(C═O)O_(r)]_(s)(C₁-C₈)alkyl, wherein the alkyl may be optionallysubstituted with one or more R¹⁴'s,

(e) —S(O)_(p)(C₁-C₈)alkyl, wherein the alkyl may be optionallysubstituted with one or more R¹⁴'s,

(f) heterocyclyl optionally substituted with one or more R¹⁴'s;

R¹⁰ is:

(a) halo,

(b) —OH,

(c) —O[(C═O)O_(r)]_(s)(C₁-C₆)-alkyl,

(d) —O[(C═O)O_(r)]_(s)(C₂-C₆)-alkenyl,

(e) —O[(C═O)O_(r)]_(s)aryl,

(f) —O[(C═O)O_(r)]_(s)heteroaryl,

(g) cyano,

(h) nitro,

(i) —NR⁸R⁹,

(j) —O(CO)NR⁸R⁹,

(k) —CO(C₁-C₆)-alkyl,

(l) —CO₂(C₁-C₆)-alkyl,

(m) —CONR⁸R⁹,

(n) aryl, which may optionally be substituted with one or moresubstituents selected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyl,    -   4) (C₁-C₄)-perfluoroalkyl,    -   5) (C₁-C₆)-alkyloxy,    -   6) cyano,    -   7) —CO(C₁-C₆)-alkyl,    -   8) —CO₂(C₁-C₆)-alkyl,    -   9) —CONR⁸R⁹,    -   10) —NR⁸R⁹,    -   11) —O(C═O)—(C₁-C₆)-alkyl, and    -   12) —O(C═O)NR⁸R⁹,

(o) heteroaryl optionally substituted with one or more substituentsselected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyl,    -   4) (C₁-C₄)-perfluoroalkyl,    -   5) (C₁-C₆)-alkyloxy,    -   6) cyano,    -   7) —CO(C₁-C₆)-alkyl,    -   8) —CO₂(C₁-C₆)-alkyl,    -   9) —CONR⁸R⁹,    -   10) —NR⁸R⁹,    -   11) —O(C═O)—(C₁-C₆)-alkyl, and    -   12) —O(C═O)NR⁸R⁹,

(p) heterocyclo other than heteroaryl which is optionally substitutedwith one or more substituents selected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyl,    -   4) (C₁-C₄)-perfluoroalkyl,    -   5) (C₁-C₆)-alkyloxy,    -   6) cyano,    -   7) —CO(C₁-C₆)-alkyl,    -   8) —CO₂(C₁-C₆)-alkyl,    -   9) —CONR⁸R⁹,    -   10) —NR⁸R⁹,    -   11) —O(C═O)—(C₁-C₆)-alkyl, and    -   12) —O(C═O)NR⁸R⁹,

(q) —(C₁-C₁₀)-alkyl, which may optionally be substituted with one ormore substituents selected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyloxy,    -   4) cyano,    -   5) —CO(C₁-C₆)-alkyl,    -   6) —CO₂(C₁-C₆)-alkyl,    -   7) —CONR⁸R⁹,    -   8) —NR⁸R⁹;    -   9) —O(C═O)—(C₁-C₆)-alkyl, and    -   10) —O(C═O)NR⁸R⁹;        R¹¹ is:

(a) halo,

(b) —OH,

(c) —O[(C═O)O_(r)]_(s)(C₁-C₆)-alkyl,

(d) —O[(C═O)O_(r)]_(s)aryl,

(e) —O[(C═O)O_(r)]_(s)heteroaryl,

(f) cyano,

(g) —NR⁸R⁹,

(h) —O(CO)NR⁸R⁹,

(i) —CO(C₁-C₆)-alkyl,

(j) —CO₂(C₁-C₆)-alkyl,

(k) —CONR⁸R⁹,

(l) aryl, which may optionally be substituted with one or moresubstituents selected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyl,    -   4) (C₁-C₄)-perfluoroalkyl,    -   5) (C₁-C₆)-alkyloxy,    -   6) cyano,    -   7) —CO(C₁-C₆)-alkyl,    -   8) —CO₂(C₁-C₆)-alkyl,    -   9) —CONR⁸R⁹,    -   10) —NR⁸R⁹,    -   11) —O(C═O)—(C₁-C₆)-alkyl, and    -   12) —O(C═O)NR⁸R⁹,

(m) heteroaryl optionally substituted with one or more substituentsselected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyl,    -   4) aryl-(C₁-C₆)alkyloxy-,    -   5) (C₁-C₄)-perfluoroalkyl,    -   6) (C₁-C₆)-alkyloxy,    -   7) cyano,    -   8) —CO(C₁-C₆)-alkyl,    -   9) —CO₂(C₁-C₆)-alkyl,    -   10) —CONR⁸R⁹,    -   11) —NR⁸R⁹,    -   12) —O(C═O)—(C₁-C₆)-alkyl, and    -   13) —O(C═O)NR⁸R⁹,

(n) heterocyclo other than heteroaryl which is optionally substitutedwith one or more substituents selected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyl,    -   4) (C₁-C₄)-perfluoroalkyl,    -   5) (C₁-C₆)-alkyloxy,    -   6) cyano,    -   7) —CO(C₁-C₆)-alkyl,    -   8) —CO₂(C₁-C₆)-alkyl,    -   9) —CONR⁸R⁹,    -   10) —NR⁸R⁹,    -   11) —O(C═O)—(C₁-C₆)-alkyl, and    -   12) —O(C═O)NR⁸R⁹,

(o) —(C₁-C₁₀)-alkyl, which may optionally be substituted with one ormore substituents selected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyloxy,    -   4) cyano,    -   5) —COOH,    -   6) —CO(C₁-C₆)-alkyl,    -   7) —CO₂(C₁-C₆)-alkyl,    -   8) —CONR⁸R⁹,    -   9) —NR⁸R⁹,    -   10) —O(C═O)—(C₁-C₆)-alkyl, and    -   11) —O(C═O)NR⁸R⁹,

(p) —O(CH₂)_(m)-heteroaryl as defined above;

R¹² is:

(a) halo,

(b) —OH,

(c) —O[(C═O)O_(r)]_(s)(C₁-C₆)-alkyl,

(d) —O[(C═O)O_(r)]_(s)aryl,

(e) —O[(C═O)O_(r)]_(s)heteroaryl,

(f) cyano,

(g) nitro,

(h) —NR⁸R⁹,

(i) —O(CO)NR⁸R⁹,

(j) —CO(C₁-C₆)-alkyl,

(k) —CO₂(C₁-C₆)-alkyl,

(l) —CONR⁸R⁹,

(m) aryl, which may optionally be substituted with one or moresubstituents selected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyl,    -   4) (C₁-C₄)-perfluoroalkyl,    -   5) (C₂-C₆)-alkenyl,    -   6) (C₂-C₆)-alkynyl,    -   7) (C₁-C₆)-alkyloxy,    -   8) cyano,    -   9) —COOH,    -   10) —CO(C₁-C₆)-alkyl,    -   11) —CO₂(C₁-C₆)-alkyl,    -   12) —CONR⁸R⁹,    -   13) —NR⁸R⁹,    -   14) —O(C═O)—(C₁-C₆)-alkyl, and    -   15) —O(C═O)NR⁸R⁹,

(n) heteroaryl optionally substituted with one or more substituentsselected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyl,    -   4) (C₁-C₄)-perfluoroalkyl,    -   5) (C₁-C₆)-alkyloxy,    -   6) cyano,    -   7) —COOH,    -   8) —CO(C₁-C₆)-alkyl,    -   9) —CO₂(C₁-C₆)-alkyl,    -   10) —CONR⁸R⁹,    -   11) —NR⁸R⁹,    -   12) —O(C═O)—(C₁-C₆)-alkyl, and    -   13) —O(C═O)NR⁸R⁹,

(o) heterocyclo other than heteroaryl which is optionally substitutedwith one or more substituents selected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyl,    -   4) (C₁-C₄)-perfluoroalkyl,    -   5) (C₁-C₆)-alkyloxy,    -   6) cyano,    -   7) —CO(C₁-C₆)-alkyl,    -   8) —CO₂(C₁-C₆)-alkyl,    -   9) —CONR⁸R⁹,    -   10) —NR⁸R⁹,    -   11) —O(C═O)—(C₁-C₆)-alkyl, and    -   12) —O(C═O)NR⁸R⁹,

(p) —(C₁-C₁₀)-alkyl, which may optionally be substituted with one ormore substituents selected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyloxy,    -   4) cyano,    -   5) —CO(C₁-C₆)-alkyl,    -   6) —CO₂(C₁-C₆)-alkyl,    -   7) —CONR⁸R⁹,    -   8) —NR⁸R⁹,    -   9) —O(C═O)—(C₁-C₆)-alkyl, and    -   10) —O(C═O)NR⁸R⁹,

(q) ═O;

R¹⁴ is:

(a) halo,

(b) —OH,

(c) —O[(C═O)O_(r)]_(s)(C₁-C₆)-alkyl,

(d) —O[(C═O)O_(r)]_(s)aryl,

(e) —O[(C═O)O_(r)]_(s)heteroaryl,

(f) cyano,

(g) nitro,

(h) —NR⁸R⁹,

(i) —O(CO)NR⁸R⁹,

(j) —CO(C₁-C₆)-alkyl,

(k) —CO₂(C₁-C₆)-alkyl,

(l) —CONR⁸R⁹,

(m) aryl, which may optionally be substituted with one or moresubstituents selected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyl,    -   4) (C₁-C₄)-perfluoroalkyl,    -   5) (C₁-C₆)-alkyloxy,    -   6) cyano,    -   7) —CO(C₁-C₆)-alkyl,    -   8) —CO₂(C₁-C₆)-alkyl,    -   9) —CONR⁸R⁹,    -   10) —NR⁸R⁹,    -   11) —O(C═O)—(C₁-C₆)-alkyl, and    -   12) —O(C═O)NR⁸R⁹,

(n) heteroaryl optionally substituted with one or more substituentsselected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyl,    -   4) (C₁-C₄)-perfluoroalkyl,    -   5) (C₁-C₆)-alkyloxy,    -   6) cyano,    -   7) —CO(C₁-C₆)-alkyl,    -   8) —CO₂(C₁-C₆)-alkyl,    -   9) —CONR⁸R⁹,    -   10) —NR⁸R⁹,    -   11) —O(C═O)—(C₁-C₆)-alkyl, and    -   12) —O(C═O)NR⁸R⁹,

(o) heterocyclo other than heteroaryl which is optionally substitutedwith one or more substituents selected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyl,    -   4) (C₁-C₄)-perfluoroalkyl,    -   5) (C₁-C₆)-alkyloxy,    -   6) cyano,    -   7) —CO(C₁-C₆)-alkyl,    -   8) —CO₂(C₁-C₆)-alkyl,    -   9) —CONR⁸R⁹,    -   10) —NR⁸R⁹,    -   11) —O(C═O)—(C₁-C₆)-alkyl, and    -   12) —O(C═O)NR⁸R⁹,

(p) —(C₁-C₁₀)-alkyl, which may optionally be substituted with one ormore substituents selected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyloxy,    -   4) cyano,    -   5) —CO(C₁-C₆)-alkyl,    -   6) —CO₂(C₁-C₆)-alkyl,    -   7) —CONR⁸R⁹,    -   8) —NR⁸R⁹,    -   9) —O(C═O)—(C₁-C₆)-alkyl, and    -   10) —O(C═O)NR⁸R⁹;        R¹⁹ is:

(a) hydrogen,

(b) (C₁-C₆)-alkyl,

(c) —CO(C₁-C₆)-alkyl,

(d) —CO(C₁-C₆)-aryl,

(e) —CO(C₁-C₆)-heteroaryl,

(f) —CO₂(C₁-C₆)-alkyl,

(g) CO₂(C₁-C₆)-aryl,

(h) CO₂(C₁-C₆)-heteroaryl, or

(i) —CONR⁸R⁹;

R²⁰ is:

(a) hydrogen,

(b) halo,

(c) —OH,

(d) —O[(C═O)O_(r)]_(s)(C₁-C₆)-alkyl,

(e) —O[(C═O)O_(r)]_(s)aryl,

(f) —O[(C═O)O_(r)]_(s)heteroaryl,

(g) cyano,

(h) nitro,

(i) —NR⁸R⁹,

(j) —O(CO)NR⁸R⁹,

(k) —CO(C₁-C₆)-alkyl,

(l) —CO₂(C₁-C₆)-alkyl,

(m) —CONR⁸R⁹,

(n) aryl, which may optionally be substituted with one or moresubstituents selected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyl,    -   4) (C₁-C₄)-perfluoroalkyl,    -   5) (C₁-C₆)-alkyloxy,    -   6) cyano,    -   7) —CO(C₁-C₆)-alkyl,    -   8) —CO₂(C₁-C₆)-alkyl,    -   9) —CONR⁸R⁹,    -   10) —NR⁸R⁹,    -   11) —O(C═O)—(C₁-C₆)-alkyl, and    -   12) —O(C═O)NR⁸R⁹,

(o) heteroaryl optionally substituted with one or more substituentsselected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyl,    -   4) (C₁-C₄)-perfluoroalkyl,    -   5) (C₁-C₆)-alkyloxy,    -   6) cyano,    -   7) —CO(C₁-C₆)-alkyl,    -   8) —CO₂(C₁-C₆)-alkyl,    -   9) —CONR⁸R⁹,    -   10) —NR⁸R⁹,    -   11) —O(C═O)—(C₁-C₆)-alkyl, and    -   12) —O(C═O)NR⁸R⁹,

(p) heterocyclo other than heteroaryl which is optionally substitutedwith one or more substituents selected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyl,    -   4) (C₁-C₄)-perfluoroalkyl,    -   5) (C₁-C₆)-alkyloxy,    -   6) cyano,    -   7) —CO(C₁-C₆)-alkyl,    -   8) —CO₂(C₁-C₆)-alkyl,    -   9) —CONR⁸R⁹, and    -   10) —NR⁸R⁹,

(q) —(C₁-C₁₀)-alkyl, which may optionally be substituted with one ormore substituents selected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyloxy,    -   4) cyano,    -   5) —CO(C₁-C₆)-alkyl,    -   6) —CO₂(C₁-C₆)-alkyl,    -   7) —CONR⁸R⁹,    -   8) —NR⁸R⁹,    -   9) —O(C═O)—(C₁-C₆)-alkyl, and    -   10) —O(C═O)NR⁸R⁹;        R²¹ is:

(a) C₁-C₁₀-alkyl optionally substituted with one or more R¹¹'s,

(b) aryl optionally substituted with one or more R¹¹'s, or

(c) heterocyclyl optionally substituted with one or more R¹¹'s;

m is 1 to 4;

p is 1 or 2;

r is 0 to 4; and

s is 0 to 3.

In another embodiment, compounds of formula I are provided wherein:

R¹ is an aryl or heterocyclic ring, which may be optionally substitutedwith one or more R¹⁰'s;

R² and R³ are independently:

(a) halo,

(b) (C₁-C₆)-alkoxy optionally substituted with one or more R¹¹'s,

(c) (C₁-C₄)-perfluoroalkyl,

(d) hydrogen,

(e) C₁-C₁₀-alkyl optionally substituted with one or more R¹¹'s,

(f) aryl optionally substituted with one or more R¹¹'s, or

(g) heterocyclyl optionally substituted with one or more R¹¹'s,

provided that both R² and R³ are not simultaneously hydrogen;

R⁴ is:

(a) hydrogen,

(b) C₁-C₁₀-alkyl,

(c) —CO(C₁-C₆)-alkyl,

(d) —CO(C₁-C₆)-aryl, or

(e) —CO(C₁-C₆)-heteroaryl;R⁵ is

Q is a O, C═O, N, NR¹⁹ or CR²⁰;T is O, S, C═O, N or NR¹⁹;X, U, V and W are independently O, C═O or CR²⁰;R⁸ and R⁹ are independently:

(a) hydrogen,

(b) —[(C═O)O_(r)]_(s)aryl, wherein the aryl may be optionallysubstituted with one or more R¹⁴'s,

(c) —[(C═O)O_(r)]_(s)(C₁-C₈)alkyl, wherein the alkyl may be optionallysubstituted with one or more R¹⁴'s,

(d) heterocyclyl optionally substituted with one or more R¹⁴'s;

R¹⁰ is:

(a) halo,

(b) —O[(C═O)O_(r)]_(s)(C₁-C₆)-alkyl,

(c) —O[(C═O)O_(r)]_(s)aryl,

(d) —O[(C═O)O_(r)]_(s)heteroaryl,

(e) cyano,

(f) nitro,

(g) aryl, which may optionally be substituted with one or moresubstituents selected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyl,    -   4) (C₁-C₄)-perfluoroalkyl,    -   5) (C₁-C₆)-alkyloxy, and    -   6) cyano,

(h) heteroaryl optionally substituted with one or more substituentsselected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyl,    -   4) (C₁-C₄)-perfluoroalkyl,    -   5) (C₁-C₆)-alkyloxy, and    -   6) cyano,

(i) heterocyclo other than heteroaryl which is optionally substitutedwith one or more substituents selected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyl,    -   4) (C₁-C₄)-perfluoroalkyl,    -   5) (C₁-C₆)-alkyloxy, and    -   6) cyano,

(j) —(C₁-C₁₀)-alkyl, which may optionally be substituted with one ormore substituents selected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyloxy, and    -   4) cyano;        R¹¹ is:

(a) halo,

(b) —OH,

(c) —O[(C═O)O_(r)]_(s)(C₁-C₆)-alkyl,

(d) —O[(C═O)O_(r)]_(s)aryl,

(e) —O[(C═O)O_(r)]_(s)heteroaryl,

(f) —NR⁸R⁹, provided that neither R⁸ nor R⁹ in this instance is —C(═O)—phenyl,

(g) —O(CO)NR⁸R⁹,

(h) aryl, which may optionally be substituted with one or moresubstituents selected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyl,    -   4) (C₁-C₄)-perfluoroalkyl,    -   5) (C₁-C₆)-alkyloxy, and    -   6) cyano,

(i) heteroaryl optionally substituted with one or more substituentsselected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyl,    -   4) aryl-(C₁-C₆)alkyloxy-,    -   5) (C₁-C₄)-perfluoroalkyl,    -   6) (C₁-C₆)-alkyloxy, and    -   7) cyano,

(j) heterocyclo other than heteroaryl which is optionally substitutedwith one or more substituents selected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyl,    -   4) (C₁-C₄)-perfluoroalkyl,    -   5) (C₁-C₆)-alkyloxy, and    -   6) cyano,

(k) —(C₁-C₁₀)-alkyl, which may optionally be substituted with one ormore substituents selected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyloxy,    -   4) cyano, and    -   5) —COOH,

(l) —O(CH₂)_(m)-heteroaryl as defined above;

R¹² is:

(a) halo,

(b) —O[(C═O)O_(r)]_(s)(C₁-C₆)-alkyl,

(c) —O[(C═O)O_(r)]_(s)aryl,

(d) —O[(C═O)O_(r)]_(s)heteroaryl,

(e) aryl, which may optionally be substituted with one or moresubstituents selected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyl,    -   4) (C₁-C₄)-perfluoroalkyl,    -   5) (C₁-C₆)-alkyloxy, and    -   6) cyano,

(f) heteroaryl optionally substituted with one or more substituentsselected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyl,    -   4) (C₁-C₄)-perfluoroalkyl,    -   5) (C₁-C₆)-alkyloxy,    -   6) cyano, and    -   7) —COOH,

(g) heterocyclo other than heteroaryl which is optionally substitutedwith one or more substituents selected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyl,    -   4) (C₁-C₄)-perfluoroalkyl,    -   5) (C₁-C₆)-alkyloxy, and    -   6) cyano,

(h) —(C₁-C₁₀)-alkyl, which may optionally be substituted with one ormore substituents selected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyloxy, and    -   4) cyano,

(i) ═O;

R¹⁴ is:

(a) halo,

(b) —OH,

(c) —O[(C═O)O_(r)]_(s)(C₁-C₆)-alkyl,

(d) —O[(C═O)O_(r)]_(s)aryl,

(e) —O[(C═O)O_(r)]_(s)heteroaryl,

(f) aryl, which may optionally be substituted with one or moresubstituents selected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyl,    -   4) (C₁-C₄)-perfluoroalkyl,    -   5) (C₁-C₆)-alkyloxy, and    -   6) cyano,

(g) heteroaryl optionally substituted with one or more substituentsselected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyl,    -   4) (C₁-C₄)-perfluoroalkyl,    -   5) (C₁-C₆)-alkyloxy, and    -   6) cyano,

(h) heterocyclo other than heteroaryl which is optionally substitutedwith one or more substituents selected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyl,    -   4) (C₁-C₄)-perfluoroalkyl,    -   5) (C₁-C₆)-alkyloxy, and    -   6) cyano,

(i) —(C₁-C₁₀)-alkyl, which may optionally be substituted with one ormore substituents selected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyloxy, and    -   4) cyano;        R¹⁹ is:

(a) hydrogen,

(b) (C₁-C₆)-alkyl,

(c) —CO(C₁-C₆)-alkyl,

(d) —CO₂(C₁-C₆)-alkyl, or

(e) —CONR⁸R⁹;

R²⁰ is:

(a) hydrogen,

(b) halo,

(c) —OH,

(d) —O[(C═O)O_(r)]_(s)(C₁-C₆)-alkyl,

(e) aryl, which may be optionally substituted with one or moresubstituents selected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyl,    -   4) (C₁-C₄)-perfluoroalkyl,    -   5) (C₁-C₆)-alkyloxy, and    -   6) cyano,

(f) heteroaryl optionally substituted with one or more substituentsselected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyl,    -   4) (C₁-C₄)-perfluoroalkyl,    -   5) (C₁-C₆)-alkyloxy, and    -   6) cyano,

(g) heterocyclo other than heteroaryl which is optionally substitutedwith one or more substituents selected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyl,    -   4) (C₁-C₄)-perfluoroalkyl,    -   5) (C₁-C₆)-alkyloxy, and    -   6) cyano,

(h) —(C₁-C₁₀)-alkyl, which may optionally be substituted with one ormore substituents selected from the group consisting of:

-   -   1) halo,    -   2) —OH,    -   3) (C₁-C₆)-alkyloxy, and    -   4) cyano;        m is 1 to 3;        r is 0 to 3; and        s is 0 to 2.

In yet another embodiment, compounds of formula I are provided wherein:

R¹ is an aryl or heterocyclic ring, which may be optionally substitutedwith one or more R¹⁰'s;

R² and R³ are independently:

(a) hydrogen,

(b) C₁-C₁₀-alkyl optionally substituted with one or more R¹¹'s,

(c) aryl optionally substituted with one or more R¹¹'s, or

(d) heterocyclyl optionally substituted with one or more R¹¹'s,

provided that both R² and R³ are not simultaneously hydrogen;

R⁴ is hydrogen or C₁-C₁₀-alkyl;

R⁵ is

Q is a O, C═O, NR¹⁹ or CR²⁰;T is O, S, C═O or NR¹⁹;X, U, V and W are independently C═O or CR²⁰;R⁸ and R⁹ are independently:

(a) hydrogen,

(b) —[(C═O)O_(r)]_(s)aryl,

(c) —[(C═O)O_(r)]_(s)(C₁-C₈)alkyl, or

(d) heterocyclyl;

R¹⁰ is:

(a) halo,

(b) —O[(C═O)O_(r)]_(s)(C₁-C₆)-alkyl,

(c) —O[(C═O)O_(r)]_(s)heteroaryl,

(d) aryl,

(e) heteroaryl,

(f) heterocyclo, or

(g) —(C₁-C₁₀)-alkyl;

R¹¹ is:

(a) —OH,

(b) —O[(C═O)O_(r)]_(s)(C₁-C₆)-alkyl,

(c) —O[(C═O)O_(r)]_(s)aryl,

(d) —O[(C═O)O_(r)]_(s)heteroaryl,

(e) —O(CO)NR⁸R⁹,

(f) aryl,

(g) heteroaryl,

(h) heterocyclo,

(i) —(C₁-C₁₀)-alkyl, or

(j) —O(CH₂)_(m)-heteroaryl as defined above;

R¹² is:

(a) halo,

(b) —O[(C═O)O_(r)]_(s)(C₁-C₆)-alkyl,

(c) —O[(C═O)O_(r)]_(s)aryl,

(d) —O[(C═O)O_(r)]_(s)heteroaryl,

(e) aryl,

(f) heteroaryl,

(g) heterocyclo,

(h) —(C₁-C₁₀)-alkyl, and

(i) ═O;

R¹⁹ is:

(a) hydrogen,

(b) (C₁-C₆)-alkyl, or

(c) —CONR⁸R⁹;

R² is:

(a) hydrogen,

(b) halo,

(c) —O[(C═O)O_(r)]_(s)(C₁-C₆)-alkyl,

(d) aryl,

(e) heteroaryl,

(f) heterocyclo,

(g) —(C₁-C₁₀)-alkyl;

m is 1 to 3;

r is 0 to 3; and

s is 0 to 2.

In one embodiment, compounds of formula I are provided wherein:

R¹ is phenyl or pyridinyl, which may be optionally-substituted with oneor more R¹⁰'s;

R² and R³ are independently:

(a) hydrogen,

(b) C₁-C₁₀-alkyl optionally substituted with one or more R¹¹'s,

(c) aryl optionally substituted with one or more R¹¹'s, or

(d) heterocyclyl optionally substituted with one or more R¹¹'s,

provided that both R² and R³ are not simultaneously hydrogen;

R⁴ is hydrogen;

R⁵ is

Q is a O, C═O or CR²⁰;T is O, S or NR¹⁹;X, U, V and W are CR²⁰;R⁸ and R⁹ are independently:

(a) hydrogen,

(b) aryl,

(c) {C₁-C₈)alkyl,

(d) heterocyclyl;

R¹⁰ is:

(a) halo,

(b) —O(C₁-C₆)-alkyl,

(c) —Oheteroaryl,

(d) aryl,

(e) heteroaryl,

(f) —(C₁-C₁₀)-alkyl;

R¹¹ is:

(a) —O(C₁-C₆)-alkyl,

(b) —Oaryl,

(c) —Oheteroaryl,

(d) —O(CO)NR⁸R⁹,

(e) aryl,

(f) heteroaryl,

(g) —(C₁-C₁₀)-alkyl;

R¹² is:

(a) halo,

(b) —O(C₁-C₆)-alkyl,

(c) —Oaryl,

(d) —Oheteroaryl,

(e) aryl,

(f) heteroaryl,

(g) —(C₁-C₁₀)-alkyl, and

(h) ═O;

R¹⁹ is:

(a) hydrogen,

(b) (C₁-C₆)-alkyl, or

(c) —CONR⁸R⁹; and

R²⁰ is:

(a) hydrogen,

(b) halo,

(c) —O(C₁-C₆)-alkyl,

(d) aryl,

(e) heteroaryl,

(f) heterocyclo, or

(g) —(C₁-C₁₀)-alkyl.

In another embodiment, compounds of the present invention are selectedfrom the compounds exemplified in Examples 1 to 72.

Synthesis

Compounds of formula I of may be prepared as shown in the followingreaction schemes and description thereof, as well as relevant literatureprocedures that may be used by one skilled in the art. Exemplaryreagents and procedures for these reactions appear hereinafter and inthe working examples set forth below.

Compounds of the formula I, where R⁵ is

T being O or NR¹⁹, and U, V and W are independently C(R²⁰)_(p) or N, maybe prepared using Scheme 1:

Aldehyde (II) is treated with hydroxylamine or an optionally substitutedhydrazine to form (III), which is then oxidized to (IV) using a reagentsuch as N-chlorosuccimide or bromine. The addition of amine (V) in thepresence of a base, such as triethyl amine, gives the coupled product(VI), which undergoes an intramolecular cyclization to give compounds offormula (I). In one embodiment, it may be necessary to inducecyclization of intermediate (VI) using a base, such as potassiumt-butoxide or sodium hydride, in a solvent, such as tetrahydrofuran(“THF”) or N,N-dimethylformamide (“DMF”), to give compounds of formula(I). Suitable Z substituents for cyclization are leaving groups such ashalides (especially fluoro), nitro, hydroxyl and methoxyl groups. (seeFink, D. M; Kurys, B. E. Tetrahedron Lett Vol 37 no 7 pp995-998, 1196).

Compounds of the formula I, where R⁵ is

T being O or NR¹⁹, and U, V and W are independently C(R²⁰)_(p) or N, maybe prepared using Scheme 2:

The amine (V) is condensed with acid (X) in the presence of a base andcoupling reagent to give amide (XI). Suitable bases that may be usedinclude, but are not limited to, tertiary amines such as triethyl amine.Suitable coupling reagents that may be used include, but are not limitedto, any of the coupling reagents commonly used in peptide synthesis, forexample, benzotriazol-1-yloxy-tris(dimethylamino)-phosphoniumhexafluorophosphate (“BOP reagent”). The amide (XI) is then converted tothe thioamide (XII) using Lawesson's-reagent. Heating thioamide (XII) inthe presence of hydroxylamine or an optionally substituted hydrazineforms compounds of formula (I). Suitable Z substituents for cyclizationare leaving groups such as halides (especially fluoro), nitro, hydroxyland methoxyl groups.

Compounds of the formula I, where R⁵ is

T being S or Q, X are independently N, NR¹⁹ or C(R²⁰)_(p), and U, V andW are independently C(R²⁰)_(p) or N, may be prepared using Scheme 3:

Displacement of a leaving group X (such as halo or triflate) on reagent(X)) by amine (V) results in formation of compounds of formula (I).Conditions may include deprotonation of the amine (V) using a strongbase such as n-butyl lithium (“n-BuLi”) in an aprotic solvent, such asTHF, followed by addition of (X) (see J. Med. Chem. 1991, 34, 3316), orthe use of a weaker base, such as potassium carbonate (“K₂CO₃”) in asolvent, such as DMF. Methods of N-arylation of amines such as (V) usingsubstrates such as (X) in the presence of transition metal catalysts,for example, copper and palladium (see Buchwald J. Org. Chem. 2000, 65,1144)), can also be employed.

Compounds of the formula I, where R⁵ is

T being C═O, and U, V and W are independently C(R²⁰)_(p) or N, may beprepared using Scheme 4:

Condensation of the amine (V) with (XI) forms compounds of formula (I).

Compounds of formula (II) are either known compounds or may be preparedby conventional methods known to one of ordinary skill in the art.Examples of suitable methods include, but are not limited to, themethods shown in Scheme 5.

Compounds of formula (V) are either known compounds or may be preparedby conventional methods known to one of ordinary skill in the art.Examples of suitable methods include, but are not limited to, themethods shown in Scheme 6.

Compounds of formula (VII) are either known compounds or may be preparedby conventional methods known by one of ordinary skill in the art.

Compounds of formula (X) are either known compounds or may be preparedby conventional methods known by one of ordinary skill in the art.Examples of suitable methods include, but are not limited to, themethods shown in Scheme 7.

Compounds of formula (XI) may be prepared by conventional methods knownto one of ordinary skill in the art. An example of a suitable methodincludes, but is not limited to, the method shown in Scheme 8.

Compounds of formula (I) may also be prepared from other compounds offormula (I) by a variety of interconversion processes.

For example, according to a general interconversion process (IP.1), forcompounds of formula (I) in which R²⁰ is a potential leaving group (suchas halo or triflate), this group can be displaced by nucleophiles (suchas alkoxides, amines or metalated variants of organic compounds) in thepresence of transition metals when required.

According to another general interconversion process (IP.2), forcompounds of formula (I) in which R⁴=H, this group can be replaced withan alkyl or acyl group by reacting with an alkyl halide (or similarvariants) or activated acid (or their variants) respectively, in thepresence of an acid or base catalyst when necessary.

According to another general interconversion process (IP.3), forcompounds of formula (I) in which R²⁰=H, this group can be replaced witha halide, especially chloro using N-chlorosuccinimide, by electrophilicaromatic substitution.

According to another general interconversion process (IP.4), forcompounds of formula (I) in which R²⁰=H, this group can be replaced withan acyl group by Friedel-Crafts acylation.

According to another general interconversion process (IP.5), forcompounds of formula (I) in which R¹² is —OCH₃, this group can beconverted to —OH by reaction with boron tribromide.

According to another general interconversion process (IP.6), forcompounds of formula (I) in which R¹⁹=H, this group can be replaced withan alkyl or acyl group by reacting with an alkyl halide (or similarvariants) or activated acid (or their variants) respectively, in thepresence of an acid or base catalyst when necessary.

According to another general interconversion process (IP.7), forcompounds of formula (I) in which Q is C(R²⁰)_(p) and this R²⁰=Cl, R²⁰can be converted to —OH by hydrolysis using aqueous acid or to NR¹⁹ byreaction with NHR¹⁹ in the presence of a transition metal catalyst whennecessary.

According to another general interconversion process (IP.8), forcompounds of formula (I) in which T=O, reduction of the N—O bond usingconditions such as hydrogenation in the presence of a catalyst followedby cyclization using doubly activated carbonyl source such as1,1′-carbonyldiimidazole, gives compounds of formula (I) with Q=C═O andX=O.

According to another general interconversion process (IP.9), forcompounds of formula (I) in which T=O, reduction of the N—O bond usingconditions such as hydrogenation in the presence of a catalyst followedby cyclization using doubly activated sulfonyl source such as1,1′-sulfonyldiimidazole, gives compounds of formula (I) with Q=SO₂ andX=O.

According to another general interconversion process (IP.10), forcompounds of formula (I) in which T=C═O, reaction with an optionallysubstituted hydrazine NH₂NHR¹⁹ gives compounds of formula (I) in whichQ=NR¹⁹ and X=C═O.

According to another general interconversion process (IP.11), forcompounds of formula (I) in which Q=NR¹⁹ and X=C═O, reaction with adehydrating agent such as phosphorous oxychloride gives compounds offormula (I) in which Q=NR¹⁹ and X=C(R²⁰)_(p) where R²⁰=Cl.

According to another general interconversion process (IP.11), forcompounds of formula (I) in which Q=NR¹⁹ and X=C(R²⁰)_(p) where R²⁰=Cl,this R²⁰=Cl may be displaced by nucleophiles (such as alkoxides andamines) to give a different R²⁰ or may be reduced by hydrogenation togive compounds where R²⁰=H.

During any of the above synthetic sequences it may be necessary toprotect certain functional groups at required steps in the sequence.This may be achieved by utilizing protecting group such as thosedescribed by T. W. Greene and P. G. M. Wuts in Protective Groups inOrganic Synthesis, John Wiley & Sons, 1991. The protecting groups may beremoved at convenient subsequent steps in the synthesis using methodsknown in the art.

Utility

Compounds within the scope of the present invention inhibit the K_(v)1subfamily of voltage-gated K+ channels, and as such are useful in thetreatment and/or prevention of various disorders: cardiac arrhythmias,including supraventricular arrhythmias, atrial arrhythmias, atrialflutter, atrial fibrillation, complications of cardiac ischemia, and useas heart rate control agents; angina pectoris including relief ofPrinzmetal's symptoms, vasospastic symptoms and variant symptoms;gastrointestinal disorders including reflux esauphagitis, functionaldispepsia, motility disorders (including constipation and diarrhea), andirritable bowel syndrome; disorders of vascular and visceral smoothmuscle including asthma, chronic obstructive pulmonary disease, adultrespiratory distress syndrome, peripheral vascular disease (includingintermittent claudication), venous insufficiency, impotence, cerebraland coronary spasm and Raynaud's disease; inflammatory and immunologicaldisease including inflammatory bowel disease, rheumatoid arthritis,graft rejection, asthma. chronic obstructive pulmonary disease, cysticfibrosis and atherosclerosis; cell poliferative disorders includingrestenosis and cancer (including leukemia); disorders of the auditorysystem; disorders of the visual system including macular degenerationand cataracts; diabetes including diabetic retinopathy, diabeticnephropathy and diabetic neuropathy; muscle disease including myotoniaand wasting; peripheral neuropathy; cognitive disorders; migraine;memory loss including Alzheimer's and dementia; CNS mediated motordysfunction including Parkinson's disease, and ataxia; epilepsy; andother ion channel mediated disorders.

As inhibitors of the K_(v)1 subfamily of voltage-gated K+ channelscompounds of the present invention are useful to treat a variety offurther disorders including resistance by transplantation of organs ortissue, graft-versus-host diseases brought about by medulla ossiumtransplantation, rheumatoid arthritis, systemic lupus erythematosus,hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type Idiabetes uveitis, juvenile-onset or recent-onset diabetes mellitus,posterior uveitis, allergic encephalomyelitis, glomerulonephritis,infectious diseases caused by pathogenicmicroorganisms, inflammatory andhyperproliferative skin diseases, psoriasis, atopical dermatitis,contact dermatitis, eczematous dermatitises, seborrhoeis dermatitis,Lichen planus, Pemphigus, bullous pemphigoid, Epidermolysis bullosa,urticaria, angioedemas, vasculitides, erythemas, cutaneouseosinophilias, Lupus erythematosus, acne, Alopecia greata,keratoconjunctivitis, vernal conjunctivitis, uveitis associated withBehcet's disease, keratitis, herpetic keratitis, conical cornea,dystrophia epithelialis corneae, corneal leukoma, ocular pemphigus,Mooren's ulcer Scleritis, Graves' opthalmopathy, Vogt-Koyanagi-Haradasyndrome, sarcoidosis, pollen allergies, reversible obstructive airwaydisease, bronchial asthma, allergic asthma, intrinsic asthma, extrinsicasthma, dust asthma, chronic or inveterate asthma, late asthma andairway hyper-responsiveness, bronchitis, gastric ulcers, vascular damagecaused by ischemic diseases and thrombosis, ischemic bowel diseases,inflammatory bowel diseases, necrotizing enterocolitis, intestinallesions associated with thermal burns and leukotriene B4-mediateddiseases, Coeliaz diseases, proctitis, eosinophilic gastroenteritis,mastocytosis, Crohn's disease, ulcerative colitis, migraine, rhinitis,eczema, interstitial nephritis, Good-pasture's syndrome,hemolytic-uremic syndrome, diabetic nephropathy, multiple myositis,Guillain-Barre syndrome, Meniere's disease, polyneuritis, multipleneuritis, mononeuritis, radiculopathy, hyperthroidism, Basedow'sdisease, pure red cell aplasia, aplastic anemia, hypoplastic anemia,idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia,agranulocytosis, pernicious anemia, megaloblastic anemia,anerythroplasia, osteoporosis, sarcoidosis, fibroid lung, idiopathicinterstitial pneumonia, dermatomyositis, leukoderma vulgaris, ichthyosisvulgaris, photoallergic sensitivity, cutaneous T cell lymphoma,arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritisnodosa, myocardosis, scleroderma, Wegener's granuloma, Sjogren'ssyndrome, adiposis, eosinophilic fascitis, lesions of gingiva,periodontium, alveolar bone, substantia osses dentis,glomerulonephritis, male pattern alopecia or alopecia senilis bypreventing epilation or providing hair germination and/or promoting hairgeneration and hair growth, muscular dystrophy; Pyoderma and Sezary'ssyndrome, Addison's disease, ischemia-reperfusion injury of organs whichoccurs upon preservation, transplantation or ischemic disease,endotoxin-shock, pseudomembranous colitis, colitis caused by drug orradiation, ischemic acute renal insufficiency, chronic renalinsufficiency, toxinosis caused by lung-oxygen or drugs, lung cancer,pulmonary emphysema, cataracta, siderosis, retinitis, pigentosa, senilemacular degeneration, vitreal scarring, corneal alkali burn, dermatitiserythema multiforme, linear IgA ballous dermatitis and cementdermatitis, gingivitis, periodontitis, sepsis, pancreatitis, diseasescaused by environmental pollution, aging, carcinogenis, metastatis ofcarcinoma and hypobaropathy, disease caused by histamine orleukotriene-C4 release, Behcet's disease, autoimmune hepatitis, primarybiliary cirrhosis sclerosing cholangitis, partial liver resection, acuteliver necrosis, necrosis caused by toxin, viral hepatitis, shock, oranoxia, B-virus hepatitis, non-A/non-B hepatitis, cirrhosis, alcoholiccirrhosis, hepatic failure, fulminant hepatic failure, late-onsethepatic failure, “acute-on-chronic” liver failure, augention ofchemotherapeutic effect, cytomegalovirus infection, HCMV infection,AIDS, cancer, senile dementia, trauma, and chronic bacterial infection.

The compounds of the present invention are antiarrhythmic agents whichare useful in the prevention and treatment (including partialalleviation or cure) of arrhythmias. As inhibitors of K_(v)1.5,compounds within the scope of the present invention are particularlyuseful in the selective prevention and treatment of supraventriculararrhythmias such as atrial fibrillation, and atrial flutter. By“selective prevention and treatment of supraventricular arrhythmias” ismeant the prevention or treatment of supraventricular arrhythmiaswherein the ratio of the prolongation of the atrial effective refractoryperiod to the prolongation of the ventricular effective refractoryperiod is greater than 1:1. This ratio can also be greater than 4:1,even greater than 10:1. In addition, the ratio may be such thatprolongation of the atrial effective refractory response period isachieved without significantly detectable prolongation of theventricular effective refractory period.

In addition, the compounds within the scope of the present inventionblock I_(Kur), and thus may be useful in the prevention and treatment ofall I_(Kur)-associated conditions. An “I_(Kur)-associated condition” isa disorder which may be prevented, partially alleviated or cured by theadministration of an I_(Kur) blocker. The K_(v)1.5 gene is known to beexpressed in stomach tissue, intestinal/colon tissue, the pulmonaryartery, and pancreatic beta cells. Thus, administration of an I_(Kur)blocker can provide useful treatment for disorders such as: refluxesauphagitis, functional dispepsia, constipation, asthma, and diabetes.Additionally, K_(v)1.5 is known to be expressed in the anteriorpituitary. Thus, administration of an I_(Kur) blocker can stimulategrowth hormone secretion. I_(Kur) inhibitors can additionally be usefulin cell poliferative disorders such as leukemia, and autoimmune diseasessuch as rheumatoid arthritis and transplant rejection.

The present invention thus provides methods for the prevention ortreatment of one or more of the aforementioned disorders, comprising thestep of administering to a subject in need thereof an effective amountof at least one compound of the formula I. Other therapeutic agents suchas those described below may be employed with the inventive compounds inthe present methods. In the methods of the present invention, such othertherapeutic agent(s) may be administered prior to, simultaneously withor following the administration of the compound(s) of the presentinvention.

The present invention also provides pharmaceutical compositionscomprising at least one of the compounds of the formula I or saltsthereof capable of preventing or treating one or more of theaforementioned disorders in an amount effective therefor, and apharmaceutically acceptable vehicle or diluent. The compositions of thepresent invention may contain other therapeutic agents as describedbelow, and may be formulated, for example, by employing conventionalsolid or liquid vehicles or diluents, as well as pharmaceuticaladditives of a type appropriate to the mode of desired administration(for example, excipients, binders, preservatives, stabilizers, flavors,etc.) according to techniques such as those well known in the art ofpharmaceutical formulation.

The compounds of the formula I may be administered by any suitablemeans, for example, orally, such as in the form of tablets, capsules,granules or powders; sublingually; bucally; parenterally, such as bysubcutaneous, intravenous, intramuscular, or intrasternal injection orinfusion techniques (e.g., as sterile injectable aqueous or non aqueoussolutions or suspensions); nasally such as by inhalation spray;topically, such as in the form of a cream or ointment; or rectally suchas in the form of suppositories; in dosage unit formulations containingnon toxic, pharmaceutically acceptable vehicles or diluents. The presentcompounds may, for example, be administered in a form suitable forimmediate release or extended release. Immediate release or extendedrelease may be achieved by the use of suitable pharmaceuticalcompositions comprising the present compounds, or, particularly in thecase of extended release, by the use of devices such as subcutaneousimplants or osmotic pumps. In the case where the compounds of formula Iare being administered to prevent or treat arrhythmias, the compoundsmay be administered to achieve chemical conversion to normal sinusrhythm, or may optionally be used in conjunction with electricalcardioconversion.

Exemplary compositions for oral administration include suspensions whichmay contain, for example, microcrystalline cellulose for imparting bulk,alginic acid or sodium alginate as a suspending agent, methylcelluloseas a viscosity enhancer, and sweeteners or flavoring agents such asthose known in the art; and immediate release tablets which may contain,for example, microcrystalline cellulose, dicalcium phosphate, starch,magnesium stearate and/or lactose and/or other excipients, binders,extenders, disintegrants, diluents and lubricants such as those known inthe art. The compounds of formula I may also be delivered through theoral cavity by sublingual and/or buccal administration. Molded tablets,compressed tablets or freeze-dried tablets are exemplary forms which maybe used. Exemplary compositions include those formulating the presentcompound(s) with fast dissolving diluents such as mannitol, lactose,sucrose and/or cyclodextrins. Also included in such formulations may behigh molecular weight excipients such as celluloses (avicel) orpolyethylene glycols (PEG). Such formulations may also include anexcipient to aid mucosal adhesion such as hydroxy propyl cellulose(HPC), hydroxy propyl methyl cellulose (HPMC), sodium carboxy methylcellulose (SCMC), maleic anhydride copolymer (e.g., Gantrez), and agentsto control release such as polyacrylic copolymer (e.g., Carbopol 934).Lubricants, glidants, flavors, coloring agents and stabilizers may alsobe added for ease of fabrication and use.

Exemplary compositions for nasal aerosol or inhalation administrationinclude solutions in saline which may contain, for example, benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, and/or other solubilizing or dispersing agents such asthose known in the art.

Exemplary compositions for parenteral administration include injectablesolutions or suspensions which may contain, for example, suitable nontoxic, parenterally acceptable diluents or solvents, such as mannitol,1,3 butanediol, water, Ringer's solution, an isotonic sodium chloridesolution, or other suitable dispersing or wetting and suspending agents,including synthetic mono- or diglycerides, and fatty acids, includingoleic acid.

Exemplary compositions for rectal administration include suppositorieswhich may contain, for example, a suitable non irritating excipient,such as cocoa butter, synthetic glyceride esters or polyethyleneglycols, which are solid at ordinary temperatures, but liquefy and/ordissolve in the rectal cavity to release the drug.

Exemplary compositions for topical administration include a topicalcarrier such as Plastibase (mineral oil gelled with polyethylene).

The effective amount of a compound of the present invention may bedetermined by one of ordinary skill in the art, and includes exemplarydosage amounts for an adult human of from about 0.001 to 100 mg/kg ofbody weight of active compound per day, which may be administered in asingle dose or in the form of individual divided doses, such as from 1to 4 times per day. It will be understood that the specific dose leveland frequency of dosage for any particular subject may be varied andwill depend upon a variety of factors including the activity of thespecific compound employed, the metabolic stability and length of actionof that compound, the species, age, body weight, general health, sex anddiet of the subject, the mode and time of administration, rate ofexcretion, drug combination, and severity of the particular condition.Preferred subjects for treatment include animals, most preferablymammalian species such as humans, and domestic animals such as dogs,cats and the like, subject to the aforementioned disorders.

The compounds of the present invention may be employed alone or incombination with each other and/or other suitable therapeutic agentsuseful in the treatment of the aforementioned disorders or otherdisorders, including: other antiarrhythmic agents such as Class I agents(e.g., propafenone), Class II agents (e.g., carvadiol and propranolol),Class III agents (e.g., sotalol, dofetilide, amiodarone, azimilide andibutilide), Class IV agents (e.g., diltiazem and verapamil), 5HTantagonists (e.g., sulamserod, serraline and tropsetron), anddronedarone; calcium channel blockers (both L-type and T-type) such asdiltiazem, verapamil, nifedipine, amlodipine and mybefradil;Cyclooxygenase inhibitors (i.e., COX-1 and/or COX-2 inhibitors) such asaspirin, indomethacin, ibuprofen, piroxicam, naproxen, celebrex, vioxxand NSAIDs; anti-platelet agents such as GPIIb/IIIa blockers (e.g.,abciximab, eptifibatide and tirofiban), P2Y12 antagonists (e.g.,clopidogrel, cangrelor, ticlopidine and CS-747), P2Y1 antagonists,thromboxane receptor antagonists (e.g., ifetroban), aspirin, and PDE-IIIinhibitors (e.g., dipyridamole) with or without aspirin; diuretics suchas chlorothiazide, hydrochlorothiazide, flumethiazide,hydroflumethiazide, bendroflumethiazide, methylchlorothiazide,trichloromethiazide, polythiazide, benzthiazide, ethacrynic acidtricrynafen, chlorthalidone, furosemide, musolimine, bumetanide,triamtrenene, amiloride, and spironolactone; anti-hypertensive agentssuch as alpha adrenergic blockers, beta adrenergic blockers, calciumchannel blockers, diuretics, renin inhibitors, ACE inhibitors, (e.g.,captropril, zofenopril, fosinopril, enalapril, ceranopril, cilazopril,delapril, pentopril, quinapril, ramipril, lisinopril), A II antagonists(e.g., losartan, irbesartan, valsartan), ET antagonists (e.g.sitaxsentan, atrsentan and compounds disclosed in U.S. Pat. Nos.5,612,359 and 6,043,265), Dual ET/AII antagonist (e.g., compoundsdisclosed in WO 00/01389), neutral endopeptidase (NEP) inhibitors,vasopepsidase inhibitors (dual NEP-ACE inhibitors) (e.g., omapatrilatand gemopatrilat), nitrates, and combinations of such anti-hypertensiveagents; antithrombotic/thrombolytic agents such as tissue plasminogenactivator (tPA), recombinant tPA, tenecteplase (TNK), lanoteplase (nPA),factor VIIa inhibitors, factor Xa inhibitors (such as razaxaban), XIainhibitors, thromin inhibitors (e.g., hirudin and argatroban), PAI-1inhibitors (i.e., inactivators of tissue plasminogen activatorinhibitors), α2-antiplasmin inhibitors, streptokinase, urokinase,prourokinase, anisoylated plasminogen streptokinase activator complex,and animal or salivary gland plasminogen activators; anticoagulants suchas warfarin and heparins (including unfractionated and low molecularweight heparins such as enoxaparin and dalteparin); HMG-CoA reductaseinhibitors such as pravastatin lovastatin, atorvastatin, simvastatin,NK-104 (a.k.a. itavastatin, or nisvastatin or nisbastatin) and ZD-4522(a.k.a. rosuvastatin, or atavastatin or visastatin); othercholesterol/lipid lowering agents such as squalene synthetaseinhibitors, fibrates, and bile acid sequestrants (e.g., questran);antipoliferative agents such as cyclosporin A, taxol, FK 506, andadriamycin; antitumor agents such as taxol, adriamycin, epothilones,cisplatin and carboplatin; anti-diabetic agents such as biguanides (e.g.metformin), glucosidase inhibitors (e.g. acarbose), insulins,meglitinides (e.g. repaglinide), sulfonylureas (e.g. glimepiride,glyburide and glipizide), biguanide/glyburide combinations (i.e.,glucovance), thiozolidinediones (e.g. troglitazone, rosiglitazone andpioglitazone), PPAR-gamma agonists, aP2 inhibitors, and DP4 inhibitors;thyroid mimetics (including thyroid receptor antagonists) (e.g.,thyrotropin, polythyroid, KB-130015, and dronedarone); Mineralocorticoidreceptor antagonists such as spironolactone and eplerinone; growthhormone secretagogues; anti-osteoporosis agents (e.g., alendronate andraloxifene); hormone replacement therapy agents such as estrogen(including conjugated estrogens in premarin), and estradiol;antidepressants such as nefazodone and sertraline; antianxiety agentssuch as diazepam, lorazepam, buspirone, and hydroxyzine pamoate; oralcontraceptives; anti-ulcer and gastroesophageal reflux disease agentssuch as famotidine, ranitidine, and omeprazole; anti-obesity agents suchas orlistat; cardiac glycosides including digitalis and ouabain;phosphodiesterase inhibitors including PDE III inhibitors (e.g.cilostazol), and PDE V inhibitors (e.g., sildenafil); protein tyrosinekinase inhibitors; steroidal anti-inflammatory agents such asprednisone, and dexamethasone; and other anti-inflammatory agents suchas enbrel. The combinations can be co-formulated or in the form of kitspackaged to provide appropriate dosages for co-administration.

The above other therapeutic agents, when employed in combination withthe compounds of the present invention, may be used, for example, inthose amounts indicated in the Physicians' Desk Reference (PDR) or asotherwise determined by one of ordinary skill in the art.

Assays to determine the degree of activity of a compound as an I_(Kur)inhibitor are well known in the art and are described in references suchas J. Gen. Physiol. April; 101(4):513-43, and Br. J. Pharmacol. 1995May; 115(2):267-74.

Assays to determine the degree of activity of a compound as an inhibitorof other members of the K_(v)1 subfamily are also well known in the art.For example, inhibition of K_(v)1.1, K_(v)1.2 and K_(v)1.3 can bemeasured using procedures described by

Grissmer S, et al., Mol Pharmacol 1994 June; 45(6):1227-34. Inhibitionof K_(v)1.4 can be measured using procedures described by Petersen K R,and Nerbonne J M, Pflugers Arch 1999 February; 437(3):381-92. Inhibitionof K_(v)1.6 can be measured using procedures described by Bowlby M R,and Levitan I B, J Neurophysiol 1995 June; 73(6):2221-9. And inhibitionof K_(v)1.7 can be measured using procedures described by Kalman K, etal., J Biol Chem 1998 Mar. 6; 273(10):5851-7.

The following examples further illustrate the present invention, but ofcourse, should not be construed as in any way limiting its scope.

Intermediates Intermediate 1 2-Methyl-2-phenylpropaneamine

To a stirred solution of 2-methyl-2-phenylpropanenitrile (prepared in asimilar manner as the preparation disclosed in J. Am. Chem. Soc. 2000,122, 712; 3.99 g, 27.5 mmol) in anhydrous THF (50 mL) was added asolution of 1.0 molar (M) lithium aluminum hydride in THF (33 mL, 33mmol). Upon completion of addition, the reaction mixture was heated toreflux where it stirred for 3 hours (“h” or “hr” or “hrs”). Uponcompletion of this period, the reaction mixture was cooled in an icebath and then carefully quenched by the addition of 4 normal (“N”)sodium hydroxide (“NaOH”, ˜5 mL) until the resulting effervescencesceased. The reaction mixture was then filtered through a pad of sodiumsulfate (“Na₂SO₄”) and the filter cake was washed with THF. The filtratewas concentrated under reduced pressure to provide Intermediate 1 as acolorless oil (4.1 g, 100%). ¹H NMR (400 MHz, deuterated chloroform(“CDCl₃”)) δ ppm 1.31 (s, 6H), 2.80 (s, 2H), 7.21 (td, J=5.82, 2.86 Hz,1H) 7.31-7.36(m, 4H).

Intermediate 2 2-(3-Methoxyphenyl)-2-methylpropan-1-amine

Intermediate 2 was prepared from2-(3-methoxyphenyl)-2-methylpropanenitrile (prepared in a similar manneras the preparation disclosed in J. Am. Chem. Soc. 2000, 122, 712) in asimilar manner as described for the preparation of Intermediate 1. ¹HNMR (400 MHz, CDCl₃) δ ppm 1.20 (s, 6H) 2.70 (s, 2H) 3.72 (s, 3H) 6.67(dd, J=8.13, 2.42 Hz, 1H) 6.80 (d, J=2.20 Hz, 1H) 6.84 (d, J=7.03 Hz,1H) 7.17 (t, J=8.13 Hz, 1H).

Intermediate 3 2-(4-Methoxyphenyl)-2-methylpropan-1-amine

Intermediate 3 was prepared from2-(4-methoxyphenyl)-2-methylpropanenitrile (prepared in a similar manneras the preparation disclosed in J. Am. Chem. Soc. 2000, 122, 712) in asimilar manner as described for the preparation of Intermediate 1. ¹HNMR (400 MHz, CDCl₃) δ ppm 1.19 (s, 6H) 2.67 (s, 2H) 3.70 (s, 3H) 6.79(d, J=8.79 Hz, 2H) 7.17 (d, J=8.79 Hz, 2H).

Intermediate 4 2-Methyl-2-(6-methylpyridin-2-yl)propanenitrile

(Intermediate 4 was prepared in a similar manner to the preparationdisclosed in J. Am. Chem. Soc. 2000, 122, 712). To a stirred solution of2-fluoro-6-methylpyridine (4.31 g, 38.8 mmol) in toluene (150 mL) wasadded isobutyronitrile (13.9 mL, 155 mmol) followed by potassiumbis(trimethylsilyl)amide (11.7 g, 59 mmol). Upon completion of addition,the reaction was heated to 80° C. for 1 h. After this time, the reactionwas cooled to ambient temperature, poured into saturated (“satd”)ammonium chloride (“NH₄Cl”, 100 mL) and then extracted with toluene(2×100 mL). The combined organics were washed with water (“H₂O”, 100mL), dried over magnesium sulphate (“Mg₂SO₄”) and filtered. Thevolatiles were removed under reduced pressure to yield a residue. Theresidue was subjected to chromatography on silica gel eluting with 5%ethyl acetate (“EtOAc”)/hexanes to provide Intermediate 4 as a paleyellow oil (4.91 g, 86%). ¹H NMR (400 MHz, CDCl₃) δ ppm 1.74 (s, 6H),2.54 (s, 3H), 7.07 (d, J=7.91 Hz, 1H), 7.37 (d, J=7.91 Hz, 1H), 7.58 (t,J=7.91 Hz, 1H).

Intermediate 5 2-Methyl-2-(pyridin-2-yl)propanenitrile

Intermediate 5 was prepared from 2-fluoropyridine and isobutyronitrilein a similar manner as described for the preparation of Intermediate 4.¹H NMR (400 MHz, CDCl₃) δ ppm 1.65 (s, 6H) 7.13 (dd, J=7.03, 5.27 Hz,1H) 7.47 (d, J=7.91 Hz, 1H) 7.62 (td, J=7.80, 1.98 Hz, 1H) 8.49 (d,J=3.95 Hz, 1H).

Intermediate 6 2-Methyl-2-(5-methylpyridin-2-yl)propanenitrile

Intermediate 6 was prepared from 2-fluoro-5-methylpyridine andisobutyronitrile in a similar manner as described for the preparation ofIntermediate 4. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.46 (s, 6H) 2.06 (s, 3H)7.18-7.21 (m, 1H) 7.25-7.29 (m, 1H) 8.13-8.16 (m, 1H).

Intermediate 72-Methyl-2-(6-(trifluoromethyl)pyridin-2-yl)propanenitrile

(Intermediate 7 was prepared in a similar manner to the preparationdescribed in Angew. Chem. Int. Ed. 2003, 42, 5051). To a stirredsolution of bis(dibenzylideneacetone)palladium (0) (“Pd₂(dba)₃”, 100 mg,0.11 mmol) and potassium t-butoxide (617 mg, 5.5 mmol) in toluene (11mL) was added2,8,9-tri-i-butyl-2,5,8,9-tetraza-1-phosphabicyclo[3.3.3]undecane (75mg, 0.22 mmol) in toluene (2 mL) followed by2-chloro-6-(trifluoromethyl) pyridine, (500 mg, 2.75 mmol). Uponcompletion of addition, the reaction mixture was stirred for 20 minutes.After this time, isobutyronitrile (0.30 mL) was added and the resultingmixture was heated at 90° C. for 5 h. Upon completion of this period,the reaction mixture was poured into H₂O (20 mL) and extracted withtoluene (3×20 mL). The combined extracts were dried over Na₂SO₄, andfiltered. The volatiles were removed under reduced pressure to provide aresidue. The residue was subjected to chromatography on silica gel using0 to 25% EtOAc/hexanes to provide Intermediate 7 as a clear oil. (120mg, 20%).

Intermediate 8 2-Methyl-2-(6-methylpyridin-2-yl)propan-1-amine

To a stirred solution of Intermediate 4 (2.4 g, 16 mmol) in ethanol (100mL) was added Raney 2800 nickel (5 mL of slurry in water). Uponcompletion of addition, the reaction mixture was stirred under hydrogengas (“H₂”) at 70 atmospheres (“atm”) for 6 h and then filtered throughcelite. The volatiles were removed under reduced pressure to provideIntermediate 8 as a clear colorless oil (1.83 g, 69%). ¹H NMR (400 MHz,CDCl₃) δ ppm 1.31 (s, 6H), 2.52 (s, 3H), 2.92 (s, 2H), 6.94 (d, J=7.47Hz, 1H), 7.09 (d, J=7.91 Hz, 1H), 7.50 (t, J=7.91 Hz, 1H).

Intermediate 92-Methyl-2-(6-(trifluoromethyl)pyridin-2-yl)propan-1-amine

Intermediate 9 was prepared from Intermediate 7 in a similar manner asdescribed for the preparation of Intermediate 8. m/z (ES⁺) 219 (M+H).

Intermediate 10 2-Methyl-2-(pyridin-2-yl)propan-1-amine

Intermediate 10 was prepared from Intermediate 5 in a similar manner asdescribed for the preparation of Intermediate 8. ¹H NMR (400 MHz, CDCl₃)δ ppm 1.34 (s, 6H), 2.95 (s, 2H) 7.09-7.13 (m, 1H) 7.32 (d, J=7.91 Hz,1H) 7.60-7.67 (m, 1H) 8.58 (d, J=3.52 Hz, 1H).

Intermediate 11 2-Methyl-2-(5-methylpyridin-2-yl)propan-1-amine

Intermediate 11 was prepared from Intermediate 6 in a similar manner asdescribed for the preparation of Intermediate 8. m/z (ES⁺) 164 (M+H).

Intermediate 12 (+/−)-3-(2-Nitro-1-phenylethyl)pentane-2,4-dione

(Intermediate 12 was prepared in a similar manner to the preparationdescribed in Synthesis 1982, 467). To a stirred solution of2,4-pentanedione (2.05 mL, 20 mmol) and β-nitrostyrene (2.98 g, 20 mmol)in chloroform (20 mL) was added nickel(II) acetylacetonate (51 mg, 0.20mmol). Upon completion of addition, the reaction mixture was heated at60° C. for 48 h. After this time, the reaction mixture was cooled toambient temperature and then filtered through celite. The volatiles wereremoved under reduced pressure to provide a residue. The residue wassubjected to chromatography on silica gel eluting with 10 to 40%EtOAc/hexanes to provide Intermediate 12 as a pale yellow solid (1.10 g,22%). ¹H NMR (400 MHz, CDCl₃) δ ppm 1.92 (s, 3H), 2.28 (s, 3H),4.19-4.23 (m, 1H), 4.33-4.37 (m, 1H), 4.57-4.66 (m, 2H), 7.14-7.18 (m,2H), 7.27-7.33 (m, 3H).

Intermediate 13 (+/−)-3,5-Dimethyl-4-(2-nitro-1-phenylethyl)-1H-pyrazole

To a suspension of Intermediate 12 (100 mg, 0.40 mmol) in methanol(“MeOH”, 3 mL) was added hydrazine monohydrate (21 uL, 0.44 mmol). Uponcompletion of addition, the reaction mixture was stirred for 16 h. Afterthis time, the volatiles were removed under reduced pressure to provideIntermediate 13 (98 mg, 99%), which was used without furtherpurification. ¹H NMR (400 MHz, CDCl₃) δ ppm 2.19 (s, 6H), 4.85-4.93 (m,2H), 5.06 (dd, J=17.14, 11.43 Hz, 1H), 7.16 (d, J=7.47 Hz, 2H),7.23-7.28 (m, 1H), 7.33 (t, J=7.25 Hz, 2H).

Intermediate 14(+/−)-1,3,5-Trimethyl-4-(2-nitro-1-phenylethyl)-1H-pyrazole

Intermediate 14 was prepared from Intermediate 12 and methylhydrazine ina similar manner as described for the preparation of Intermediate 13. ¹HNMR (400 MHz, CDCl₃) δ ppm 2.13 (s, 3H), 2.15 (s, 3H), 3.70 (s, 3H),4.85-4.93 (m, 2H), 5.06 (dd, J=17.14, 11.43 Hz, 1H), 7.16 (d, J=7.47 Hz,2H), 7.23-7.28 (m, 1H), 7.33 (t, J=7.25 Hz, 2H).

Intermediate 15 (+/−)-3,5-Dimethyl-4-(2-nitro-1-phenylethyl)isoxazole

To a suspension of Intermediate 12 (100 mg, 0.40 mmol) in hot t-butylalcohol (“t-BuOH”, 5 mL) was added hydroxylamine hydrochloride (31 mg,0.44 mmol). Upon completion of addition, the reaction mixture was heatedat reflux where it stirred for 3 h. After this time, the reactionmixture was cooled to ambient temperature. Once at the prescribedtemperature, the volatiles were removed under reduced pressure toprovide a residue. The residue was brought up into EtOAc (25 mL), washedwith a satd sodium bicarbonate solution (“NaHCO₃”, 10 ml) and brine (10mL), dried over MgSO₄, and filtered. Once again, the volatiles wereremoved under reduced pressure to provide Intermediate 15 as a brownsolid (105 mg), which was used without further purification. ¹H NMR (400MHz, CDCl₃) δ ppm 2.13 (s, 3H), 2.38 (s, 3H), 4.79-4.90 (m, 2H), 5.03(dd, J=11.86, 6.15 Hz, 1H), 7.14 (d, J=7.03 Hz, 2H), 7.23-7.28 (m, 1H),7.30-7.38 (m, 2H).

Intermediate 16(+/−)-2-(3,5-Dimethyl-1H-pyrazol-4-yl)-2-phenylethanamine

To a stirred solution of Intermediate 13 (98 mg, 0.40 mmol) in methanol(3 mL) was added 10% palladium on carbon (catalytic amount). Uponcompletion of addition, the reaction mixture was stirred under H₂ (1atm) for 3 days. After this time, the reaction mixture was filteredthrough celite to provide Intermediate 16, which was used withoutfurther purification.

Intermediate 17(+/−)-2-Phenyl-2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethanamine

Intermediate 17 was prepared from Intermediate 14 in a similar manner asdescribed for the preparation of Intermediate 16.

Intermediate 18 (+/−)-2-(3,5-Dimethylisoxazol-4-yl)-2-phenylethanamine

Intermediate 18 was prepared from Intermediate 15 in a similar manner asdescribed for the preparation of Intermediate 16.

Intermediate 19 3,6-Difluoro-2-methoxybenzaldehyde

To a stirred solution of 2,5-difluoroanisole (570 mg, 4.0 mmol) in THF(4 mL) at −78° C. was added dropwise a 1.4M solution of secondary butyllithium (“sec-BuLi”) in hexane (3.0 mL, 4.2 mmol). Upon completion ofaddition, the reaction mixture was stirred for 0.5 h and then DMF (0.38mL, 4.9 mmol) was added at such a rate as to keep the temperature below−70° C. After addition was complete, the reaction mixture was stirredfor 0.5 h and then allowed to warm to ambient temperature over a 0.5 hperiod. Once at the prescribed temperature, the reaction mixture wasquenched by the addition of 3N HCl (6 mL) and then extracted withdiethyl ether (“Et₂O”, 3×30 mL). The combined organics were washed withH₂O (15 mL), brine (15 mL), dried over Na₂SO₄, and filtered. Thevolatiles were removed under reduced pressure to provide a residue. Theresidue was subjected to chromatography on silica gel eluting with 0 to10% EtOAc/hexanes to provide Intermediate 19 as a pale yellow oil (530mg, 76%). ¹H NMR (400 MHz, CDCl₃) δ ppm 4.01 (s, 3H), 6.73 (td, J=9.34,3.30 Hz, 1H), 7.21 (ddd, J=10.99, 9.23, 4.83 Hz, 1H), 10.26 (s, 1H).

Intermediate 20 2-Fluoro-3,6-dimethoxybenzaldehyde

To a stirred solution of 2-fluoro-1,4-dimethoxybenzene (500 mg, 3.2mmol) in THF (10 mL) at −78° C. was added dropwise a 2.5M solution ofn-BuLi in hexane (1.28 mL, 3.2 mmol). The reaction mixtured was stirredfor 1 h, and then DMF (0.27 mL, 3.5 mmol) was added at such a rate as tokeep the temperature below −70° C. Upon completion of addition, thereaction mixture was stirred for 3 h and then quenched at −78° byaddition of a solution of acetic acid (“HOAc”) in THF. Water was addedand the reaction mixture was extracted with ethyl acetate. The organicextracts were dried over MgSO₄, filtered, and the solvent was removedunder reduced pressure to provide Intermediate 20 as a yellow solid (518mg, 88%), which was used without further purification.

Intermediate 21 6-Fluoro-2,3-dimethoxybenzaldehyde

Intermediate 21 was prepared from 4-fluoro-1,2-dimethoxybenzene in asimilar manner as described for the preparation of Intermediate 20. ¹HNMR (400 MHz, CDCl₃) δ ppm 3.88 (s, 3H), 3.98 (s, 3H), 6.85 (t, J=9.45Hz, 1H), 7.09 (dd, J=9.23, 5.27 Hz, 1H), 10.39 (s, 1H).

Intermediates 22a AND 22b 4-Chloro-2-fluoro-6-methoxybenzaldehyde and2-chloro-6-fluoro-4-methoxybenzaldehyde

A mixture of intermediates 22a and 22b was prepared from1-chloro-3-fluoro-5-methoxybenzene in a similar manner as described forthe preparation of Intermediate 20.

Intermediate 23 3,5-Dimethoxypyridine

To a vial charged with 2,5-difluoropyridine (127 mg, 1.1 mmol) was addeda 25% solution of sodium methoxide in methanol (2 mL). Upon completionof addition, the reaction mixture was heated at 135° C. under microwaveconditions for 15 min. At the conclusion of this period, the reactionmixture was diluted with brine (5 mL) and extracted with EtOAc (3×5 mL).The combined extracts were dried over Na₂SO₄ and filtered. The volatileswere removed under reduced pressure to provide a residue. The residuewas subjected to chromatography on silica gel eluting with 0 to 60%EtOAc/hexanes to provide Intermediate 23 as a yellow oil (139 mg, 91%).¹H NMR (400 MHz, CDCl₃) δ ppm 3.80 (s, 6H), 6.87 (t, J=2.20 Hz, 1H),7.78 (d, J=2.20 Hz, 2H).

Intermediate 24 3,5-dimethoxyisonicotinaldehyde

To a stirred solution of lithium diisopropylamide (“LDA”, 1.2 mmol) inTHF (4 mL) at −78° C. was added a solution of Intermediate 23 (139 mg,1.0 mmol) at a rate which kept the temperature below −70° C. Thereaction mixture was stirred for 30 minutes and then DMF (0.12 mL, 1.5mmol) was added dropwise. Upon completion of addition, the reactionmixture was stirred for 1 h and then diluted with EtOAc (10 mL). Theresulting mixture was washed with satd NaHCO₃ (5 mL), brine (5 mL),dried over Na₂SO₄ and filtered. The volatiles were removed under reducedpressure to provide a residue. The residue was subjected tochromatography on silica gel eluting with 0 to 70% EtOAc/hexanes toprovide Intermediate 24 as a pale yellow solid (75 mg, 45%). ¹H NMR (400MHz, CDCl₃) δ ppm 3.95 (s, 6H), 8.11 (s, 2H), 10.44 (s, 1H).

Intermediate 25 4,6-Dimethoxypyrimidine-5-carbaldehyde

Intermediate 25 was prepared from 4,6-dimethoxypyrimidine in a similarmanner as described for the preparation of Intermediate 21. ¹H NMR (400MHz, CDCl₃) δ ppm 4.09 (s, 6H), 8.51 (s, 1H), 10.35 (s, 1H).

Intermediates 26A AND 26B 2,6-Difluoro-4-methoxybenzaldehyde and2,4-difluoro-6-methoxybenzaldehyde

(Intermediates 26A and 26B were prepared in a similar manner to thepreparation described in WO 2004046133). To a stirred solution of3,5-difluoroanisole (1.0 g, 7.0 mmol) in dichloromethane (6 mL) at 0° C.was added dropwise titanium tetrachloride (1.23 mL, 11.2 mmol) anddichloromethyl methyl ether (0.63 mL, 7.0 mmol). Upon completion ofaddition, the reaction mixture was stirred for 1 h and then poured intoice-water (50 mL). The resulting mixture was extracted withdichloromethane (3×50 mL). The combined organics were washed with H₂O(50 mL), brine (50 mL), dried over Na₂SO₄ and filtered. The volatileswere removed under reduced pressure to provide a residue. The residuewas subjected to chromatography on silica gel eluting with 0 to 20%EtOAc/hexanes to give 2,6-difluoro-4-methoxybenzaldehyde, Intermediate26A [less polar material, 230 mg, 19%, ¹H NMR (400 MHz, CDCl₃) δ ppm3.85 (s, 3H), 6.47 (d, J=10.55 Hz, 2H), 10.17 (s, 1H)] and2,4-difluoro-6-methoxybenzaldehyde, Intermediate 26B [more polarmaterial, 740 mg, 62%, ¹H NMR (400 MHz, CDCl₃) δ ppm 3.91 (s, 3H)6.43-6.51 (m, 2H) 10.30 (s, 1H)], both as white solids.

Intermediate 27 2-Ethyl-6-fluorobenzaldehyde

To a vial charged with 2-chloro-6-fluorobenzaldehyde (158 mg, 1.0 mmol),2,4,6-trivinylcyclotriboroxane pyridine complex (380 mg, 1.0 mmol),tetrakis(triphenylphosphine)palladium(0) (52 mg, 5 mol %) and potassiumcarbonate (280 mg, 2.0 mmol) was added a 3:1 mixture of1,2-dimethoxyethane and water-(2 mL). Upon completion of addition, thereaction was heated at 180° C. for 1 h under microwave conditions andthen diluted with EtOAc (5 mL). The resulting mixture was washed withsatd NaHCO₃ (5 mL), dried over Na₂SO₄ and filtered. The volatiles wereremoved under reduced pressure to provide crude2-fluoro-6-vinylbenzaldehyde. The crude 2-fluoro-6-vinylbenzaldehyde wasdissolved in methanol (5 mL) and 10% palladium on carbon was added. Theresulting reaction mixture was stirred under an atmosphere of H₂ for 3 hand then filtered through celite. Once again, the volatiles were removedunder reduced pressure to provide Intermediate 27 (approximately 300 mg)as a pale yellow oil, which was used without further purification.

Intermediate 28 5-Methoxyquinazoline-2,4(1H,3H)-dione

To a suspension of 2-amino-6-methoxybenzoic acid (1.25 g, 7.5 mmol) in amixture of H₂O (45 mL) and acetic acid (0.75 mL) at 35° C. was added asolution of sodium cyanate (1.2 g, 18 mmol) in H₂O (5 mL). The reactionmixture was stirred for 0.5 h and then NaOH (13 g, 330 mmol) was addedin small portions to provide a precipitate. After cooling to roomtemperature, the pH of the reaction mixture was adjusted to 7 withconcentrated HCl. The resulting precipitate was filtered, washedthoroughly with water and dried in an oven to provide Intermediate 28 asa white solid (1.0 g, 69%) ¹H NMR (400 MHz, (CD₃)₂SO) δ ppm 3.80 (s,3H), 6.68-6.71 (m, 2H), 7.49 (t, J=8.35 Hz, 1H), 10.88 (s, 1H), 10.98(s, 1H).

Intermediate 29 2,4-Dichloro-5-methoxyquinazoline

To a flask charged with Intermediate 28 (310 mg, 1.6 mmol) was addedphosphorous oxychloride (10 mL) followed by N,N-dimethylaniline (0.2mL). Upon completion of addition, the reaction mixture was heated atreflux for 4 h. The volatiles were then removed from the reactionmixture under reduced pressure to provide a residue. To the residue wasadded satd NaHCO₃ followed by EtOAc. The organic layer was separated,dried over Na₂SO₄ and filtered. The volatiles were removed under reducedpressure to provide another residue. This residue was subject tochromatography on silica gel eluting with 10 to 20% EtOAc/hexanes toprovide Intermediate 29 as a white solid (180 mg, 49%). ¹H NMR (400 MHz,CDCl₃) δ ppm 4.03 (s, 3H), 7.02 (d, J=8.35 Hz, 1H), 7.55 (d, J=8.35 Hz,1H), 7.85 (t, J=8.35 Hz, 1H).

Intermediate 30 (+/−)-4-(benzyloxy)-2-(3-fluorophenyl)butanenitrile

To a stirred solution of 3-fluorophenylacetonitrile (1.0 ml, 8.6 mmol)in toluene (20 ml) at 60° C. was added 50% sodium amide (“NaNH₂”, 1.0ml, 13 mmol) in one portion. The resulting solution was stirred for 10min and then a solution of 2-benzyloxyethyl bromide (1.2 ml, 8.0 mmol)in toluene (20 ml) was added dropwise over a 0.5 h period. Uponcompletion of addition, the reaction mixture was stirred for anadditional 1 h. At the conclusion of this period, the reaction mixturewas cooled to ambient temperature and then quenched by adding a fewdrops of aq. 1N hydrochloric acid (“HCl”). The reaction mixture was thendiluted with EtOAc (100 ml) and washed with brine (20 ml×2). The organiclayer was separated, dried over MgSO₄ and concentrated under reducedpressure to provide an oily mixture. The oily mixture was purified onsilica eluting with 0-50% EtOAc/hexanes to provide Intermediate 30 (0.78g, 2.9 mmol, 36%) as a colorless oil.

Intermediate 31 (+/−)-4-(benzyloxy)-2-(3-fluorophenyl)butan-1-amine

To a stirred solution of Intermediate 30 (3.5 g, 13 mmol) and cobalt(II)chloride hexahydrate (“CoCl₂.6H₂O”, 6.1 g, 26 mmol) in MeOH (50 ml) wasadded sodium borohydride (“NaBH₄”, 2.5 g, 65 mmol) in several portionsover a 2 h period. The resulting dark solution was stirred for 12 h at25° C. After this time, the reaction mixture was concentrated underreduced pressure to provide a dark solid. The dark solid was partitionedat aq. ammonium hydroxide (“NH₄OH”, 50 ml) and EtOAc (200 ml). Theaqueous and organic layers were separated and the aqueous layer wasfurther washed with EtOAc (50 ml×2). The organic layers were combined,washed with brine, dried over MgSO₄ and concentrated under reducedpressure to provide Intermediate 31 a yellow oil, which was used in thefollowing reaction without further purification.

Intermediate 32 (+/−)-4-amino-3-(3-fluorophenyl)butan-1-ol

A methanolic solution of Intermediate 31 (0.5 g, 1.8 mmol) was stirredwith 10% palladium on carbon (“Pd/C”, catalytic amount) under H₂ atambient temperature for 12 h. At the conclusion of this period, thereaction mixture was filtered and concentrated under reduced pressure toprovide Intermediate 32 (0.31 g, 94%) as a colorless oil.

Intermediate 33 (+/−)-4-(benzyloxy)-2-phenylbutanenitrile

Intermediate 33 was prepared from phenylacetonitrile in a similar manneras described for the preparation of Intermediate 30.

Intermediate 34 (+/−)-4-(benzyloxy)-2-phenylbutan-1-amine

Intermediate 34 was prepared from Intermediate 33 in a similar manner asdescribed for the preparation of Intermediate 31.

Intermediate 35 (+/−)-4-amino-3-phenylbutan-1-ol

Intermediate 35 was prepared from Intermediate 34 in a similar manner asdescribed for the preparation of Intermediate 32.

Intermediate 36 Methyl 2-amino-3-methoxybenzoate

2-amino-3-methoxybenzoic acid (22.8 g, 137 mmol) was suspended in amixture of benzene (300 mL) and methanol (120 mL) and a 2M solution ofTMS-diazomethane in hexane was added dropwise until a yellow colorremained and the evolution of nitrogen stopped (˜90 mL). The solvent wasevaporated to afford Intermediate 36 (25.2 g) as a brown solid which wasused with out further purification. ¹H NMR (400 MHz, CDCl₃) δ ppm 3.87(s, 6H), 6.01 (bs, 2H), 6.58 (t, J=7.91 Hz, 1H), 6.85 (d, J=7.91 Hz,1H), 7.47 (d, J=7.91 Hz, 1H).

Intermediate 37 Methyl 2-cyano-3-methoxybenzoate

A suspension of methyl-2-amino-3-methoxybenzoate (Intermediate 36, 2.27g, 12.5 mmol) in water (10 mL) and con. HCl (2 mL) was cooled to 0 deg.C. and a solution of sodium nitrite (1.04 g, 15 mmol) in water (10 mL)was added dropwise. The resulting solution was stirred cold for 30 min.then added to a suspension of copper(I)cyanide (3.4 g, 38 mmol) in water(100 mL). The resulting suspension was heated at 60 deg. C. for 3 h,cooled, chloroform was added and the mixture was filtered throughcelite. The organic layer was dried (MgSO4), the solvent was evaporatedand the residue was flash chromatographed eluting with 0-50%hexane-ethyl acetate affording Intermediate 37 (0.56 g, 23.5%) as ayellow solid. ¹H NMR (400 MHz, CDCl₃) δ ppm 3.99 (s, 6H), 7.20 (d,J=8.35 Hz, 1H), 7.61 (t, J=8.13 Hz, 1H), 7.68 (d, J=7.47 Hz, 1H).

Intermediate 38 3-Imino-4-methoxyisoindolin-1-one

A suspension of methyl-2-cyano-3-methoxybenzoate (Intermediate 37, 570mg, 2.98 mmol) in methanol (20 mL) was saturated with anhydrous ammoniaand stirred for three days. The solvent was evaporated to giveIntermediate 38 (430 mg, 97%) as a yellow solid which was used withoutfurther purification. ¹H NMR (400 MHz, (CD₃)₂SO)) δ ppm 3.88 (s, 3H),7.19 (d, J=7.47 Hz, 1H), 7.29 (d, J=8.35 Hz, 1H), 7.56 (t, J=7.91 Hz,1H), 8.55-8.78 (bs, 1H), 10.28-10.55 (bs, 1H).

EXAMPLES Example 14-Methoxy-N-(2-methyl-2-phenylpropyl)benzo[d]isoxazol-3-amine

Compound B: To a flask charged with 2-fluoro-6-methoxylbenzaldehyde(Compound A, 2.43 g, 15.8 mmol) and hydroxylamine hydrochloride(“NH₂OH.HCl”, 1.2 g, 17.3 mmol) in ethanol (60 mL) and H₂O (120 mL) wasadded-aq. NaOH (50% w/w 3.2 mL). The reaction mixture was stirred atroom temperature for 1 hour. At the conclusion of this period, thereaction was neutralized with concentrated HCl to pH 7 and thenextracted with methylene chloride (“CH₂Cl₂”, 3×200 mL). The combinedorganic layers were washed with brine (100 mL), dried over Na₂SO₄ andfiltered. The volatiles were removed under reduced pressure to provide2-fluoro-6-methoxybenzaldehyde oxime, Compound B, as a white solid (2.45g, 92%). m/z (ES⁺) 169 (M+H).

Compound C: A portion of Compound B (100 mg, 0.59 mmol) was dissolved inDMF (2.5 mL) and then N-chlorosuccinimide (79 mg, 0.59 mmol) was added.Upon completion of addition, the reaction mixture was heated at 50° C.for 30 minutes. At the conclusion of this period, the reaction mixturewas over ice and then diluted with EtOAc (15 mL). The resulting mixturewas washed with H₂O (3×8 mL) and brine (8 mL), dried over Na₂SO₄ andfiltered. The volatiles were removed under reduced pressure to provide aresidue containing 2-fluoro-6-methoxybenzoyl chloride oxime, Compound C,as a clear oil (133 mg).

Compound E: The residue containing Compound C was taken up in anhydrous1,4-dioxane (2 mL) and then a solution of Intermediate 1 (Compound D, 88mg, 0.59 mmol) in 1,4-dioxane (1 mL) was added followed by triethylamine(90 μL, 0.65 mmol). The reaction was stirred at room temperatureovernight and then diluted with H₂O (2 mL). The resulting mixture wasextracted with Et₂O (3×5 mL), and the combined organic layers were driedover Na₂SO₄ and filtered. The volatiles were removed under reducedpressure to provide a residue. The residue was subjected tochromatography on silica gel eluting with 20 to 100% EtOAc/hexanes toprovide2-fluoro-N′-hydroxy-6-methoxy-N-(2-methyl-2-phenylpropyl)benzamidine,Compound E, as clear oil (135 mg, 72% for 2 steps). ¹H NMR (400 MHz,CDCl₃) δ ppm 1.25 (s, 6H), 3.00 (d, J=6.15 Hz, 2H), 3.83 (s, 3H), 5.23(t, J=6.15 Hz, 1H), 6.68-6.77 (m, 2H), 7.19-7.24 (m, 1H) 7.29-7.38 (m,5H).

Example 1: To a solution of Compound E (135 mg, 0.43 mmol) in THF (4 mL)was added potassium tert-butoxide (53 mg, 0.47 mmol). The reaction washeated at reflux for 2 hours and then allowed to cool to ambienttemperature. Once at the prescribed temperature, the reaction mixturewas diluted with H₂O (4 mL) and extracted with EtOAc (3×8 mL). Thecombined organic layers were dried over Na₂SO₄ and filtered. Thevolatiles were removed under reduced pressure to provide a residue. Theresidue was subjected to chromatography in silica gel eluting with 0% to40% EtOAc/hexanes to provide Example 1 as a clear oil (105 mg, 83%). ¹HNMR (400 MHz, CDCl₃) δ ppm 1.46 (s, 6H), 3.54 (d, J=6.15 Hz, 2H), 3.74(s, 3H), 4.66 (t, J=5.49 Hz, 1H), 6.43 (d, J=7.91 Hz, 1H), 6.91 (d,J=8.35 Hz, 1H), 7.24-7.33 (m, 2H), 7.38 (t, J=7.69 Hz, 2H), 7.44-7.47(m, 2H).

Example 2 (R)-4-Methoxy-N-(2-phenylpropyl)benzo[d]isoxazol-3-amine

Example 2 was prepared from 2-fluoro-6-methoxylbenzaldehyde and(R)-2-phenylpropan-1-amine in a similar manner as described for thepreparation of Example 1. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.37 (d, J=7.03Hz, 3H), 3.16-3.25 (m, 1H), 3.42 (ddd, J=12.74, 8.57, 3.74 Hz, 1H),3.60-3.67 (m, 1H), 3.79 (s, 3H), 4.87 (bs, 1H), 6.46 (d, J=7.91 Hz, 1H),6.93 (d, J=8.35 Hz, 1H) 7.24-7.33 (m, 6H).

Example 3 (S)-4-Methoxy-N-(2-phenylpropyl)benzo[d]isoxazol-3-amine

Example 3 was prepared from 2-fluoro-6-methoxylbenzaldehyde and(S)-2-phenylpropan-1-amine in a similar manner as described for thepreparation of Example 1. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.37 (d, J=7.03Hz, 3H), 3.16-3.25 (m, 1H), 3.42 (ddd, J=12.74, 8.57, 3.74 Hz, 1H),3.60-3.67 (m, 1H), 3.79 (s, 3H), 4.87 (bs, 1H), 6.46 (d, J=7.91 Hz, 1H),6.93 (d, J=8.35 Hz, 1H) 7.24-7.33 (m, 6H).

Example 4(+/−)-N-(2-(4-chlorophenyl)propyl)-4-methoxybenzo[d]isoxazol-3-amine

Example 4 was prepared from 2-fluoro-6-methoxylbenzaldehyde and(+/−)-2-(4-chlorophenyl)propan-1-amine in a similar manner as describedfor the preparation of Example 1. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.33 (d,J=7.03 Hz, 3H) 3.21 (dq, J=7.25, 7.10 Hz, 1H) 3.38 (ddd, J=12.85, 8.46,4.17 Hz, 1H) 3.59 (ddd, J=12.96, 6.81, 6.59 Hz, 1H) 3.81 (s, 3H) 4.84(bs, 1H) 6.46 (d, J=7.91 Hz, 1H) 6.92 (d, J=8.35 Hz, 1H) 7.17-7.34 (m,5H).

Example 5(+/−)-4-Methoxy-N-(2-phenyl-2-(1,3,5-trimethyl-1H-pyrazol-4-yl)ethyl)benzo[d]isoxazol-3-amine

Example 5 was prepared from 2-fluoro-6-methoxylbenzaldehyde andIntermediate 17 in a similar manner as described for the preparation ofExample 1. ¹H NMR (400 MHz, CDCl₃) δ ppm 2.00 (s, 3H), 2.08 (s, 3H),3.66 (s, 3H), 3.69-3.78 (m, 1H), 3.77 (s, 3H), 4.04-4.11 (m, 1H), 4.34(dd, J=9.23, 6.59 Hz, 1H), 4.89 (dd, J=6.59, 4.83 Hz, 1H), 6.42 (d,J=7.91 Hz, 1H), 6.89 (d, J=8.35 Hz, 1H), 7.15 (t, J=6.81 Hz, 1H),7.19-7.30 (m, 5H).

Example 6(+/−)-N-(2-(3,5-dimethyl-1H-pyrazol-4-yl)-2-phenylethyl)-4-methoxybenzo[d]isoxazol-3-amine

Example 6 was prepared from 2-fluoro-6-methoxylbenzaldehyde andIntermediate 16 in a similar manner as described for the preparation ofExample 1. ¹H NMR (400 MHz, CDCl₃) δ ppm 2.17 (s, 6H), 3.79-3.87 (m,1H), 3.82 (s, 3H), 4.12 (ddd, J=12.96, 6.81, 6.59 Hz, 1H), 4.45 (dd,J=8.79, 7.03 Hz, 1H), 4.94 (bt, J=5.71 Hz, 1H), 6.48 (d, J=7.91 Hz, 1H),6.95 (d, J=8.35 Hz, 1H), 7.19-7.36 (m, 6H).

Example 7(+/−)-N-(2-(3,5-dimethylisoxazol-4-yl)-2-phenylethyl)-4-methoxybenzo[d]isoxazol-3-amine

Example 7 was prepared from 2-fluoro-6-methoxylbenzaldehyde andIntermediate 18 in a similar manner as described for the preparation ofExample 1. ¹H NMR (400 MHz, CDCl₃) δ ppm 2.06 (s, 3H), 2.31 (s, 3H),3.80-3.87 (m, 1H), 3.84 (s, 3H), 4.10 (dt, J=13.18, 6.59 Hz, 1H),4.37-4.42 (m, 1H), 4.94 (t, J=5.71 Hz, 1H), 6.50 (d, J=7.91 Hz, 1H),6.96 (d, J=8.35 Hz, 1H), 7.22-7.28 (m, 3H), 7.30-7.38 (m, 3H).

Example 84-Methoxy-N-(2-(3-methoxyphenyl)-2-methylpropyl)benzo[d]isoxazol-3-amine

Example 8 was prepared from 2-fluoro-6-methoxylbenzaldehyde andIntermediate 2 in a similar manner as described for the preparation ofExample 1. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.37 (s, 6H), 3.44 (d, J=5.71Hz, 2H), 3.69 (s, 3H), 3.76 (s, 3H), 4.63 (t, J=5.49 Hz, 1H), 6.37 (d,J=7.91 Hz, 1H), 6.74 (dd, J=7.91, 2.20 Hz, 1H), 6.84 (d, J=8.35 Hz, 1H),6.93 (t, J=1.98 Hz, 1H), 6.97 (d, J=7.91 Hz, 1H), 7.19-7.24 (m, 2H).

Example 94-Methoxy-N-(2-(4-methoxyphenyl)-2-methylpropyl)benzo[d]isoxazol-3-amine

Example 9 was prepared from 2-fluoro-6-methoxylbenzaldehyde andIntermediate 3 in a similar manner as described for the preparation ofExample 1. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.36 (s, 6H), 3.43 (d, J=6.15Hz, 2H), 3.70 (s, 3H), 3.75 (s, 3H), 4.61 (t, J=5.49 Hz, 1H), 6.37 (d,J=8.35 Hz, 1H), 6.83-6.87 (m, 3H), 7.24 (t, J=8.13 Hz, 1H), 7.28-7.32(m, 2H).

Example 104-Methoxy-N-(2-methyl-2-(pyridin-2-yl)propyl)benzo[d]isoxazol-3-amine

Example 10 was prepared from 2-fluoro-6-methoxylbenzaldehyde andIntermediate 10 in a similar manner as described for the preparation ofExample 1. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.46 (s, 6H), 3.65 (d, J=6.15Hz, 2H), 3.86 (s, 3H), 5.99 (t, J=5.49 Hz, 1H), 6.46 (d, J=7.91 Hz, 1H),6.90 (d, J=8.35 Hz, 1H), 7.15 (dd, J=7.03, 5.27 Hz, 1H), 7.26-7.32 (m,1H), 7.38 (d, J=8.35 Hz, 1H), 7.66 (td, J=7.80, 1.98 Hz, 1H), 8.59 (d,J=3.95 Hz, 1H).

Example 114-Methoxy-N-(2-methyl-2-(5-methylpyridin-2-yl)propyl)benzo[d]isoxazol-3-amine

Example 11 was prepared from 2-fluoro-6-methoxylbenzaldehyde andIntermediate 11 in a similar manner as described for the preparation ofExample 1. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.43 (s, 6H), 2.31 (s, 3H),3.60 (d, J=5.71 Hz, 2H), 3.86 (s, 3H), 6.00 (t, J=5.49 Hz, 1H), 6.45 (d,J=8.35 Hz, 1H), 6.89 (d, J=8.35 Hz, 1H), 7.24-7.31 (m, 2H), 7.46 (dd,J=8.35, 2.20 Hz, 1H), 8.40 (d, J=2.20 Hz, 1H).

Example 124-Methoxy-N-(2-methyl-2-(6-methylpyridin-2-yl)propyl)benzo[d]isoxazol-3-amine

Example 12 was prepared from 2-fluoro-6-methoxylbenzaldehyde andIntermediate 8 in a similar manner as described for the preparation ofExample 1. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.44 (s, 6H), 2.60 (s, 3H),3.63 (d, J=6.15 Hz, 2H), 3.91 (s, 3H), 6.37 (t, J=5.27 Hz, 1H), 6.50 (d,J=7.91 Hz, 1H), 6.93 (d, J=8.35 Hz, 1 H), 7.00 (d, J=7.47 Hz, 1H), 7.16(d, J=7.91 Hz, 1H), 7.32 (t, J=8.13 Hz, 1H), 7.55 (t, J=7.69 Hz, 1H).

Example 134-Methoxy-N-(2-methyl-2-(6-(trifluoromethyl)pyridin-2-yl)propyl)benzo[d]isoxazol-3-amine

Example 13 was prepared from 2-fluoro-6-methoxylbenzaldehyde andIntermediate 9 in a similar manner as described for the preparation ofExample 1. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.48 (s, 6H) 3.76 (d, J=6.15Hz, 2H) 3.86 (s, 3H) 5.85 (t, J=6.15 Hz, 1H) 6.48 (d, J=7.91 Hz, 1H)6.92 (d, J=8.35 Hz, 1H) 7.32 (t, J=8.13 Hz, 1H) 7.55 (d, J=7.47 Hz, 1H)7.59 (d, J=7.91 Hz, 1H) 7.85 (t, J=7.91 Hz, 1H).

Example 147-Fluoro-4-methoxy-N-(2-methyl-2-phenylpropyl)benzo[d]isoxazol-3-amine

Example 14 was prepared from 2,3-difluoro-6-methoxybenzaldehyde andIntermediate 1 in a similar manner as described for the preparation ofExample 1. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.37 (s, 6H), 3.45 (d, J=6.15Hz, 2H), 3.63 (s, 3H), 4.60 (t, J=5.71 Hz, 1H), 6.21 (dd, J=8.79, 2.20Hz, 1H), 6.90-6.96 (m, 1H), 7.16-7.21 (m, 1H), 7.31 (t, J=7.69 Hz, 2H),7.34-7.39 (m, 2H).

Example 156-Fluoro-4-methoxy-N-(2-methyl-2-phenylpropyl)benzo[d]isoxazol-3-amine

Example 15 was prepared from Intermediate 26B and Intermediate 1 in asimilar manner as described for the preparation of Example 1. ¹H NMR(400 MHz, CDCl₃) δ ppm 1.44 (s, 6H), 3.50 (d, J=5.71 Hz, 2H), 3.72 (s,3H), 4.50-4.57 (m, 1H), 6.22 (dd, J=10.99, 1.76 Hz, 1H), 6.61 (dd,J=8.35, 1.76 Hz, 1H), 7.24-7.28 (m, 1H), 7.38 (t, J=7.69 Hz, 2H),7.42-7.46 (m, 2H).

Example 164-Fluoro-6-methoxy-N-(2-methyl-2-phenylpropyl)benzo[d]isoxazol-3-amine

Example 16 was prepared from Intermediate 26A and Intermediate 1 in asimilar manner as described for the preparation of Example 1. ¹H NMR(400 MHz, CDCl₃) ppm 1.38 (s, 6H), 3.48 (d, J=6.15 Hz, 2H), 3.75 (s,6H), 4.03 (bs, 1H), 6.31 (dd, J=11.42, 1.76 Hz, 1H), 6.53 (d, J=2.20 Hz,1H), 7.16-7.23 (m, 1H), 7.29-7.38 (m, 4H).

Example 175-Fluoro-4-methoxy-N-(2-methyl-2-phenylpropyl)benzo[d]isoxazol-3-amine

Example 17 was prepared from Intermediate 19 and Intermediate 1 in asimilar manner as described for the preparation of Example 1. ¹H NMR(500 MHz, CDCl₃) δ ppm 1.44 (s, 6H), 3.52 (d, J=6.05 Hz, 2H), 3.85 (d,J=3.30 Hz, 3H), 4.55 (bs, 1H), 6.85 (dd, J=8.80, 2.75 Hz, 1H), 7.11 (dd,J=12.65, 9.35 Hz, 1H), 7.23-7.28 (m, 1H), 7.38 (t, J=7.97 Hz, 2H),7.42-7.45 (m, 2H).

Example 18 4-Chloro-N-(2-methyl-2-phenylpropyl)benzo[d]isoxazol-3-amine

Example 18 was prepared from 2-chloro-6-nitrobenzaldehyde andIntermediate 1 in a similar manner as described for the preparation ofExample 1. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.48 (s, 6H), 3.58 (d, J=5.71Hz, 2H), 4.73 (bs, 1H), 7.05 (d, J=7.47 Hz, 1H), 7.24-7.41 (m, 5H),7.43-7.48 (m, 2H).

Example 194,7-Dimethoxy-N-(2-methyl-2-phenylpropyl)benzo[d]isoxazol-3-amine

Example 19 was prepared from Intermediate 20 and Intermediate 1 in asimilar manner as described for the preparation of Example 1. ¹H NMR(400 MHz, CDCl₃) δ ppm 1.45 (s, 6H), 3.53 (d, J=6.15 Hz, 2H), 3.68 (s,3H), 3.93 (s, 3H), 4.68 (t, J=5.93 Hz, 1H), 6.31 (d, J=8.35 Hz, 1H),6.76 (d, J=8.35 Hz, 1H), 7.24-7.28 (m, 1H), 7.38 (t, J=7.47 Hz, 2H),7.43-7.47 (m, 2H); mass spec m/z 326 (M+H).

Example 204-Fluoro-7-methoxy-N-(2-methyl-2-phenylpropyl)benzo[d]isoxazol-3-amine

Example 20 was prepared from Intermediate 21 and Intermediate 1 in asimilar manner as described for the preparation of Example 1. ¹H NMR(400 MHz, CDCl₃) δ ppm 1.45 (s, 6H), 3.58 (d, J=6.15 Hz, 2H), 3.96 (s,3H), 4.20 (m, 1H) 6.65 (t, J=9.01 Hz, 1H), 6.77 (dd, J=9.0, 3.95 Hz, 1H)7.26 (m, 1H) 7.35-7.45 (m, 4H); mass spec m/z 315 (M+H).

Example 214,5-Dimethoxy-N-(2-methyl-2-phenylpropyl)benzo[d]isoxazol-3-amine

Example 21 was prepared from Intermediate 21 and Intermediate 1 in asimilar manner as described for the preparation of Example 1. ¹H NMR(400 MHz, Solvent) δ ppm 1.46 (s, 6H), 3.55 (d, J=5.71 Hz, 2H), 3.71 (s,3H), 3.82 (s, 3H), 4.62 (m, 1H) 6.94 (d, J=8.79 Hz, 1H) 7.07 (d, J=8.79Hz, 1H) 7.23-7.28 (m, 1H) 7.38 (m, 2H), 7.45 (m, 2H); mass spec m/z 326(M+H).

Example 224-Methoxy-N-(2-methyl-2-phenylpropyl)isoxazolo[5,4-c]pyridin-3-amine

Example 22 was prepared from Intermediate 23 and Intermediate 1 in asimilar manner as described for the preparation of Example 1. ¹H NMR(400 MHz, CDCl₃) δ ppm 1.39 (s, 6H), 3.48 (d, J=6.15 Hz, 2H), 3.81 (s,3H), 4.51 (t, J=5.49 Hz, 1H), 7.18-7.23 (m, 1H), 7.31-7.39 (m, 4H), 7.84(s, 1H), 8.38 (s, 1H).

Example 23 4-Ethyl-N-(2-methyl-2-phenylpropyl)benzo[d]isoxazol-3-amine

Example 23 was prepared from Intermediate 27 and Intermediate 1 in asimilar manner as described for the preparation of Example 1. ¹H NMR(400 MHz, CDCl₃) δ ppm 0.91 (t, J=7.69 Hz, 3H), 1.42 (s, 6H), 2.42 (q,J=7.62 Hz, 2H), 3.52 (d, J=5.71 Hz, 2H), 3.76 (bs, 1H), 6.77 (d, J=7.03Hz, 1H), 7.12 (d, J=8.35 Hz, 1H), 7.17-7.25 (m, 2H), 7.31 (t, J=7.69 Hz,2H), 7.37-7.41 (m, 2H).

Example 246-Chloro-4-methoxy-N-(2-methyl-2-phenylpropyl)benzo[d]isoxazol-3-amine

Example 24 was prepared from Intermediate 22a and Intermediate 1 in asimilar manner as described for the preparation of Example 1. ¹H NMR(400 MHz, CDCl₃) δ ppm 1.44 (s, 6H), 3.50 (d, J=6.15 Hz, 2H), 3.73 (s,3H), 4.54 (m, 1H), 6.44 (s, 1H), 6.93 (s, 1H), 7.26 (m, 1H), 7.37 (m,2H), 7.43 (m, 2H); mass spec m/z 331 (M+H).

Example 254-Chloro-6-methoxy-N-(2-methyl-2-phenylpropyl)benzo[d]isoxazol-3-amine

Example 25 was prepared from Intermediate 22b and Intermediate 1 in asimilar manner as described for the preparation of Example 1. ¹H NMR(400 MHz, CDCl₃) δ ppm 1.45 (s, 6H), 3.53 (d, J=6.05 Hz, 2H), 3.81 (s,3H), 4.58 (m, 1H) 6.67 (s, 1H), 6.69 (s, 1H), 7.26 (m, 1H), 7.36 (t,J=7.70 Hz, 2H) 7.44 (d, J=7.70 Hz, 2H); mass spec m/z 331 (M+H).

Example 264-Methoxy-N-(2-methyl-2-phenylpropyl)isoxazolo[5,4-d]pyrimidin-3-amine

Example 26 was prepared from Intermediate 25 and Intermediate 1 in asimilar manner as described for the preparation of Example 1. ¹H NMR(400 MHz, CDCl₃) δ ppm 1.38 (s, 6H), 3.48 (d, J=6.15 Hz, 2H), 3.96 (s,3H), 4.26 (bs, 1H), 7.17-7.23 (m, 1H), 7.28-7.38 (m, 4H), 8.50 (s, 1H).

Example 274,6-Dimethoxy-N-(2-methyl-2-phenylpropyl)benzo[d]isoxazol-3-amine

To a vial charged with Example 15 (25 mg, 0.080 mmol) was added asolution of 25% sodium methoxide in methanol (2 mL). Upon completion ofaddition, the reaction mixture was heated at 125° C. for 6 minutes undermicrowave conditions. After this time, the reaction mixture was dilutedwith CH₂Cl₂ (4 mL), washed with H₂O (2 mL) and brine (2 mL), dried overNa₂SO₄ and filtered. The volatiles were removed under reduced pressureto provide a residue. The residue was subjected to chromatography onsilica gel eluting with 0% to 15% EtOAc/hexanes to provide Example 27 asa clear colorless oil (22 mg, 85%). ¹H NMR (400 MHz, CDCl₃) δ ppm 1.44(s, 6H), 3.51 (d, J=6.15 Hz, 2H), 3.69 (s, 3H), 3.80 (s, 3H), 4.51 (t,J=5.71 Hz, 1H), 6.06 (s, 1H), 6.39 (d, J=1.76 Hz, 1H), 7.24-7.28 (m,1H), 7.38 (t, J=7.69 Hz, 2H), 7.43-7.47 (m, 2H).

Example 284,7-Dichloro-N-(2-methyl-2-phenylpropyl)benzo[d]isoxazol-3-amine

Example 28 was prepared from 3,6-dichloro-2-methoxybenzoic acid andIntermediate 1 in a similar manner as described for the preparation ofExample 64 utilizing hydroxylamine in place of methyl hydrazine in thefinal step in which cyclization was conducted using sodium hydride inTHF. ¹H NMR (500 MHz, CDCl₃) δ ppm 1.47 (s, 6H) 3.54-3.59 (m, 2H) 4.75(bs, 1H) 6.99 (d, J=8.35 Hz, 1H) 7.24-7.28 (m, 1H), 7.32-7.47 (m, 5H).

Example 294-Methoxy-N-methyl-N-(2-methyl-2-phenylpropyl)benzo[d]isoxazol-3-amine

To a stirred solution of Example 1 (26 mg, 0.088 mmol) in DMF (1 mL) at0° C. was added a 60% dispersion of sodium hydride (“NaH”) in oil (3.5mg, 0.09 mmol). The reaction mixture was stirred for 15 minutes and theniodomethane (16 uL, 0.26 mmol) was added. Upon completion of addition,the reaction mixture was allowed to warm to ambient temperature where itstirred overnight. The reaction mixture was then diluted with EtOAc (20mL), washed with H₂O (3×5 mL) and brine (5 mL), dried over Na₂SO₄ andfiltered. The volatiles were removed under reduced pressure to provide aresidue. The residue was subjected to chromatography on silica geleluting with 10% EtOAc/hexanes to provide Example 29 as a clearcolorless oil (13 mg, 48%). ¹H NMR (400 MHz, CDCl₃) δ ppm 1.34 (s, 6H),2.75 (s, 3H), 3.90 (s, 2H), 3.93 (s, 3H), 6.58 (d, J=7.91 Hz, 1H), 7.01(d, J=8.35 Hz, 1H), 7.16 (t, J=7.47 Hz, 1H), 7.26-7.30 (m, 2H), 7.37 (t,J=8.13 Hz, 1H), 7.42 (d, J=7.47 Hz, 2H).

Examples 30 and 315-Chloro-4-methoxy-N-(2-methyl-2-phenylpropyl)benzo[d]isoxazol-3-amineand7-chloro-4-methoxy-N-(2-methyl-2-phenylpropyl)benzo[d]isoxazol-3-amine

To a stirred solution of Example 1 (78 mg, 0.26 mmol) in DMF (1 mL) wasadded N-chlorosuccinimide (35 mg, 0.26 mmol). Upon completion ofaddition, the reaction mixture was heated at 50° C. for 2 h. After thistime, the reaction mixture was diluted with EtOAc (5 mL), washed withH₂O (3×2 mL) and brine (2 mL), dried over Na₂SO₄ and filtered. Thevolatiles were removed under reduced pressure to provide a residue. Theresidue was subjected to chromatography on silica gel eluting with 5 to10% EtOAc/hexanes to provide5-chloro-4-methoxy-N-(2-methyl-2-phenylpropyl)benzo[d]isoxazol-3-amine,Example 30, as a clear colorless oil [less polar compound, 45 mg, 52%,¹H NMR (500 MHz, CDCl₃) δ ppm 1.46 (s, 6H), 3.56 (d, J=6.05 Hz, 2H),3.63 (s, 3H), 4.50 (t, J=5.50 Hz, 1H), 7.01 (d, J=8.80 Hz, 1H), 7.26 (t,J=7.42 Hz, 1H), 7.33 (d, J=8.80 Hz, 1H), 7.38 (t, J=7.70 Hz, 2H),7.43-7.46 (m, 2H)] and7-chloro-4-methoxy-N-(2-methyl-2-phenylpropyl)benzo[d]isoxazol-3-amine,Example 31, as a white solid [more polar compound, 23 mg, 27%, ¹H NMR(500 MHz, CDCl₃) δ ppm 1.45 (s, 6H), 3.53 (d, J=6.05 Hz, 2H), 3.72 (s,3H), 4.64 (t, J=5.77 Hz, 1H), 6.37 (d, J=8.80 Hz, 1H), 7.24-7.27 (m,2H), 7.38 (t, J=7.97 Hz, 2H), 7.42-7.46 (m, 2H)].

Examples 32 and 335-Chloro-4-methoxy-N-(2-methyl-2-(6-methylpyridin-2-yl)propyl)benzo[d]isoxazol-3-amineand7-chloro-4-methoxy-N-(2-methyl-2-(6-methylpyridin-2-yl)propyl)benzo[d]isoxazol-3-amine

5-Chloro-4-methoxy-N-(2-methyl-2-(6-methylpyridin-2-yl)propyl)benzo[d]isoxazol-3-amine,Example 32 [a clear colorless oil, less polar compound, ¹H NMR (400 MHz,CDCl₃) δ ppm 1.45 (s, 6H), 2.62 (s, 3H), 3.61 (d, J=5.71 Hz, 2H), 3.93(s, 3H), 6.70 (bt, J=5.49 Hz, 1H), 7.01-7.06 (m, 2H), 7.16 (d, J=7.91Hz, 1H), 7.38 (d, J=8.79 Hz, 1H), 7.56 (t, J=7.91 Hz, 1H)] and7-chloro-4-methoxy-N-(2-methyl-2-(6-methylpyridin-2-yl)propyl)benzo[d]isoxazol-3-amine,Example 33 [a white solid, more polar compound, ¹H NMR (400 MHz, CDCl₃)δ ppm 1.43 (s, 6H), 2.59 (s, 3H), 3.62 (d, J=6.15 Hz, 2H), 3.90 (s, 3H),6.44 (d, J=8.35 Hz, 1H), 6.48 (bs, 1H), 7.01 (d, J=7.91 Hz, 1H), 7.15(d, J=7.91 Hz, 1H), 7.29 (d, J=8.35 Hz, 1H), 7.55 (t, J=7.91 Hz, 1H)],were prepared from Example 12 in a similar manner as described for thepreparation of Example 29.

Examples 33 and 345-Bromo-4-methoxy-N-(2-methyl-2-phenylpropyl)benzo[d]isoxazol-3-amineand7-bromo-4-methoxy-N-(2-methyl-2-phenylpropyl)benzo[d]isoxazol-3-amine

5-Bromo-4-methoxy-N-(2-methyl-2-phenylpropyl)benzo[d]isoxazol-3-amine,Example 33 [a clear colorless oil, less polar compound, ¹H NMR (400 MHz,CDCl₃) δ ppm 1.45 (s, 6H), 3.54-3.58 (m, 5H), 4.46 (t, J=5.71 Hz, 1H),6.96 (d, J=8.79 Hz, 1H), 7.22-7.26 (m, 1H), 7.36 (t, J=7.69 Hz, 2H),7.44 (t, J=8.13 Hz, 3H)], and7-bromo-4-methoxy-N-(2-methyl-2-phenylpropyl)benzo[d]isoxazol-3-amine,Example 34 [a white solid, more polar compound, ¹H NMR (400 MHz, CDCl₃)8 ppm 1.44 (s, 6H), 3.52 (d, J=6.15 Hz, 2H), 3.71 (s, 3H), 4.63 (t,J=5.71 Hz, 1H), 6.32 (d, J=8.35 Hz, 1H), 7.24-7.28 (m, 1H), 7.35-7.45(m, 5H)], were prepared from Example 1 in a similar manner as describedfor the preparation of Example 29 using N-bromosuccinimide in place ofN-chlorosuccinimide.

Example 35 N-(2-Methyl-2-phenylpropyl)-4-vinylbenzo[d]isoxazol-3-amine

To a vial charged with Example 18 (30 mg, 0.10 mmol),2,4,6-trivinylcyclotriboroxane pyridine complex (38 mg, 0.1 mmol),tetrakis(triphenylphosphine)palladium(0) (5 mg, 5 mol %) and potassiumcarbonate (28 mg, 0.20 mmol) was added a 3:1 mixture of1,2-dimethoxyethane and water (1 mL). The reaction mixture was heated at180° C. under microwave conditions for 20 minutes. After this time, thereaction mixture was diluted with EtOAc (5 mL), washed with satd NaHCO₃(5 mL), dried over Na₂SO₄ and filtered. The volatiles were removed underreduced pressure to provide a residue. The residue was subjected tochromatography on silica gel eluting with 0 to 6% EtOAc/hexanes toprovide Example 35 as a clear colorless oil (9 mg, 31%). ¹H NMR (400MHz, CDCl₃) δ ppm 1.40 (s, 6H), 3.51 (d, J=5.27 Hz, 2H), 3.94 (s, 1H),5.13 (d, J=10.99 Hz, 1H), 5.34 (d, J=18.46 Hz, 1H), 6.58 (dd, J=17.58,10.99 Hz, 1H), 6.95 (d, J=7.47 Hz, 1H), 7.17-7.22 (m, 2H), 7.27-7.39 (m,5H).

Example 36 3-(2-Methyl-2-phenylpropylamino)benzo[d]isoxazol-4-ol

To a stirred solution of Example 1 (30 mg, 0.10 mmol) in1,2-dichloroethane (1 mL) was added boron tribromide dimethylsulfidecomplex (125 mg, 0.4 mmol). Upon completion of addition, the reactionmixture was heated at 190° C. under microwave conditions for 10 minutes.At the conclusion of this period, the reaction mixture was diluted withCH₂Cl₂ (5 mL), washed with satd NaHCO₃ (5 mL), dried over Na₂SO₄ andfiltered. The volatiles were removed under reduced pressure to provide aresidue. The residue was subjected to preparative High PerformanceLiquid Chromatography (“HPLC”, YMC ODS, 5 u 30×100 mm column, with flowrate of 40 mL/min over 10 min period. 50 to 100% Solvent B. SolventA=10/90/0.1% MeOH/H₂O/trifluoroacetic acid (“TFA”). SolventB=90/10/0.1%.) to provide Example 36 as a white film (2 mg, 7%). ¹H NMR(400 MHz, CD₃OD) δ ppm 1.43 (s, 6H), 3.49 (s, 2H), 6.42 (d, J=7.91 Hz,1H), 6.74 (d, J=8.35 Hz, 1H), 7.20-7.26 (m, 2H), 7.35 (t, J=7.91 Hz,2H), 7.47 (d, J=8.35 Hz, 2H).

Example 374-Methoxy-N-(2-methyl-2-phenylpropyl)-7-(1H-pyrazol-4-yl)benzo[d]isoxazol-3-amine

Example 37 was prepared from Example 34 and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in a similarmanner as described for the preparation of Example 35. ¹H NMR (400 MHz,CDCl₃) δ ppm 1.40 (s, 6H), 3.49 (d, J=6.15 Hz, 2H), 3.70 (s, 3H), 4.67(bt, J=5.93 Hz, 1H), 6.43 (d, J=8.35 Hz, 1H), 7.17-7.24 (m, 2H), 7.32(t, J=7.91 Hz, 2H), 7.37-7.42 (m, 2H), 7.46 (d, J=8.35 Hz, 1H), 8.12 (s,2H).

Example 384-Methoxy-N-(2-methyl-2-phenylpropyl)-5-(1H-pyrazol-4-yl)benzo[d]isoxazol-3-amine

Example 38 was prepared from Example 33 and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole in a similarmanner as described for the preparation of Example 35. ¹H NMR (400 MHz,CDCl₃) δ ppm 1.42 (s, 6H), 3.24 (s, 3H), 3.55 (d, J=5.71 Hz, 2H), 4.49(t, J=5.49 Hz, 1H), 6.11 (bs, 1H), 7.06 (d, J=8.35 Hz, 1H), 7.17-7.22(m, 1H), 7.32 (t, J=7.69 Hz, 2H), 7.41 (t, J=7.91 Hz, 3H), 7.88 (s, 2H).

Examples 39 and 40N-(4-methoxybenzo[d]isoxazol-3-yl)-N-(2-methyl-2-phenylpropyl)formamideand4-methoxy-3-(2-methyl-2-phenylpropylamino)benzo[d]isoxazole-7-carbaldehyde

Examples 39 and 40 were prepared from Example 1 in a similar manner asdescribed for the preparation of Intermediate 23 to give as the majorproductN-(4-methoxybenzo[d]isoxazol-3-yl)-N-(2-methyl-2-phenylpropyl)formamide,Example 39 [a clear colorless oil, less polar compound, ¹H NMR (400 MHz,CDCl₃) δ ppm 1.37 (s, 6H), 3.98 (s, 3H), 4.33 (s, 2H), 6.60 (d, J=7.91Hz, 1H), 6.83 (t, J=7.25 Hz, 1H), 6.95 (t, J=7.69 Hz, 2H), 7.01 (d,J=8.35 Hz, 1H), 7.21 (d, J=7.47 Hz, 2H), 7.42 (t, J=8.35 Hz, 1H), 8.55(s, 1H)] and4-methoxy-3-(2-methyl-2-phenylpropylamino)benzo[d]isoxazole-7-carbaldehyde,Example 40 [a white solid, more polar compound, ¹H NMR (400 MHz, CDCl₃)δ ppm 1.46 (s, 6H), 3.55 (d, J=6.15 Hz, 2H), 3.84 (s, 3H), 4.63 (bs,1H), 6.58 (d, J=8.35 Hz, 1H), 7.25-7.30 (m, 1H), 7.39 (t, J=7.69 Hz,2H), 7.43-7.48 (m, 2H), 7.90 (d, J=8.35 Hz, 1H), 10.25 (s, 1H)].

Example 414-Methoxy-1-methyl-N-(2-methyl-2-phenylpropyl)-1H-indazol-3-amine

Hydrozone B: To a solution of 2-fluoro-6-methoxybenzaldehye (Compound A,154 mg, 1.0 mmol) in ethanol (5 mL) was added N-methyl hydrazine (46 mg,1.0 mmol). The reaction mixture was heated at reflux for 1 h and thenallowed to cool to ambient temperature. Once at the prescribedtemperature, the volatiles were removed under reduced pressure toprovide a residue. The residue was brought up into H₂O (5 mL) andextracted with Et₂O (3×5 mL). The combined organic extracts were driedover MgSO₄ and then filtered. The volatiles were removed under reducedpressure to provide crude hydrazone B (165 mg, 0.91 mmol, 91%).

Compound C: The hydrazone B was dissolved in carbon tetrachloride (5mL). The resulting solution was cooled to −15° C. and then a solution ofbromine (38 uL, 0.74 mmol) in carbon tetrachloride (10 mL) was addeddropwise at such a rate as to maintain the temperature at −15° C. Uponcompletion of addition, the reaction mixture was allowed to warm toambient temperature. Once at the prescribed temperature, the reactionmixture was stirred for 1 h and then the solvent was decanted to providethe 1-(bromo(2-fluoro-6-methoxyphenyl)methylene)-2-methylhydrazinehydrobromide salt, Compound C.

Example 41: Compound C was triturated with carbon tetrachloride (5 ml)to provide a residue. To the residue of C was added dioxane (8 mL). Theresulting mixture was cooled in an ice-bath and then a solution ofIntermediate 1 (Compound D, 270 mg, 1.8 mmol) in dioxane (2 mL) followedby triethylamine (0.14 mL, 1.0 mmol) were added. Upon completion ofaddition, the reaction mixture was allowed to warm to ambienttemperature where it stirred overnight. At the conclusion of thisperiod, the reaction was diluted with satd NaHCO₃ (5 mL) and extractedwith Et₂O (3×5 mL). The combined organic extracts were dried over Na₂SO₄and filtered. The volatiles were removed under reduced pressure toprovide a residue. The residue was subject to chromatography on silicagel eluting with 5 to 40% EtOAc/hexanes to provide Example 41 as a whitesolid (52 mg, 17%). ¹H NMR (400 MHz, CDCl₃) δ ppm 1.46 (s, 6H), 3.53 (d,J=6.15 Hz, 2H), 3.69 (s, 3H), 3.75 (s, 3H), 4.46 (bt, J=5.71 Hz, 1H),6.14 (d, J=7.91 Hz, 1H), 6.65 (d, J=8.35 Hz, 1H), 7.10-7.15 (m, 1H),7.21-7.26 (m, 1H), 7.36 (t, J=7.69 Hz, 2H), 7.47 (d, J=7.03 Hz, 2H).

Example 42 4-Methoxy-N-(2-methyl-2-phenylpropyl)-1H-indazol-3-amine

Example 42 was prepared from Intermediate 1 in a similar manner asdescribed for the preparation of Example 64 utilizing hydrazine in thefinal step. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.46 (s, 6H), 3.55 (d, J=6.15Hz, 2H), 3.72 (s, 3H), 4.58 (bt, J=5.93 Hz, 1H), 6.23 (d, J=7.47 Hz,1H), 6.78 (d, J=7.91 Hz, 1H), 7.15 (t, J=7.91 Hz, 1H), 7.22-7.27 (m,1H), 7.37 (t, J=7.69 Hz, 2H), 7.47 (d, J=7.47 Hz, 2H).

Example 431-Isopropyl-4-methoxy-N-(2-methyl-2-phenylpropyl)-1H-indazol-3-amine

To a stirred solution of Example 42 (16 mg, 0.054 mmol) in DMF (0.5 mL)was added potassium carbonate (8.3 mg, 0.06 mmol) followed by2-bromopropane (18 uL, 0.12 mmol). Upon completion of addition, thereaction mixture was heated at 100° C. for 6 h. At the conclusion ofthis period, the reaction mixture was subjected to preparative HPLC(Rt=7.76 minutes using YMC ODS 5 u 30×100 mm column with flow rate of 40mL/min over 10 min period; 20 to 100% Solvent B. Solvent A=10/90/0.1%MeOH/H₂O/TFA. Solvent B=90/10/0.1%) to provide Example 43 as a pink film(1.3 mg, 7%). ¹H NMR (500 MHz, CDCl₃) δ ppm 1.44 (s, 6H), 1.45 (s, 3H),1.47 (s, 3H), 3.56 (s, 2H), 3.69 (s, 3H), 6.14 (d, J=7.70 Hz, 1H), 6.73(d, J=8.80 Hz, 1H), 7.09 (t, J=7.97 Hz, 1H), 7.21-7.24 (m, 1H), 7.35 (t,J=7.70 Hz, 2H), 7.47 (d, J=8.25 Hz, 2H).

Example 444-Methoxy-N-(2-methyl-2-phenylpropyl)benzo[d]isothiazol-3-amine

To a stirred solution of Intermediate 1 (93 mg, 0.62 mmol) in THF (6 mL)at −78° C. was added a solution of 1.6 M n-BuLi in hexane (0.39 mL, 0.62mmol) at a rate which kept the temperature below −70° C. Upon completionof addition, a solution of 3-chloro-4-methoxybenzo[d]isothiazole(prepared in a similar manner as the preparation described in J. Med.Chem. 1991, 34, 3316; 50 mg, 0.25 mmol) in THF (1.5 mL) was added at arate which kept the temperature below −70° C. The reaction mixture wasthen allowed to warm to 0° C. Once at the prescribed temperature, thereaction mixture was quenched with satd NH₄Cl (5 mL). The organic layerwas evaporated on the rotovap and the aqueous layer was extracted withCH₂Cl₂ (3×10 mL). The combined organic extracts were dried over MgSO₄and filtered. The volatiles were removed under reduced pressure toprovide a residue. The residue was subjected to chromatography on silicagel eluting with 0 to 20% EtOAc/hexanes to provide Example 44 as a clearcolorless oil (15 mg, 19%). ¹H NMR (400 MHz, CDCl₃) δ ppm 1.45 (s, 6H),3.66 (s, 3H), 3.73 (d, J=5.27 Hz, 2H), 6.06 (bt, J=5.05 Hz, 1H), 6.53(d, J=7.47 Hz, 1H), 7.21-7.29 (m, 3H), 7.38 (t, J=7.69 Hz, 2H), 7.47 (d,J=7.47 Hz, 2H).

Example 454-Methoxy-N-(2-methyl-2-(6-methylpyridin-2-yl)propyl)benzo[d]isothiazol-3-amine

Example 45 was prepared from Intermediate 8 in a similar manner asdescribed for the preparation of Example 44. ¹H NMR (400 MHz, CDCl₃) δppm 1.45 (s, 6H), 2.58 (s, 3H), 3.82-3.85 (m, 5H), 6.60 (d, J=7.47 Hz,1H), 6.92 (bt, J=5.05 Hz, 1H), 6.99 (d, J=7.47 Hz, 1H), 7.18 (d, J=7.91Hz, 1H), 7.23-7.32 (m, 2H), 7.54 (t, J=7.69 Hz, 1H).

Example 46 8-Methoxy-N-(2-methyl-2-phenylpropyl)isoquinolin-1-amine

To a vial charged with Intermediate 1 (18 mg, 0.12 mmol),1-chloro-8-methoxyisoquinoline (prepared in a similar manner as thepreparation described in Heterocycles 1996, 42, 415; 20 mg, 0.10 mmol),tris(dibenzylideneacetone)dipalladium (0) (3.7 mg, 4 mol %),2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (5 mg, 8 mol %) and sodiumt-butoxide (14 mg, 0.14 mmol) was added toluene (0.5 mL). Uponcompletion of addition, the reaction mixture was heated at 75° C. for 14h. After this time, the reaction mixture was diluted with brine (5 mL),extracted with Et₂O (3×5 mL), dried over Na₂SO₄ and filtered. Thevolatiles were removed under reduced pressure to provide a residue. Theresidue was subjected to chromatography on silica gel eluting with 25%EtOAc/hexanes to provide Example 46 as a yellow solid (24 mg, 77%). ¹HNMR (400 MHz, CDCl₃) δ ppm 1.46 (s, 6H), 3.53 (s, 3H), 3.83 (d, J=4.83Hz, 2H), 6.62 (d, J=7.91 Hz, 1H), 6.69 (d, J=5.71 Hz, 1H), 7.12 (d,J=7.47 Hz, 1H), 7.22-7.29 (m, 1H), 7.31-7.40 (m, 4H), 7.49 (d, J=8.35Hz, 2H), 7.88 (d, J=5.71 Hz, 1H).

Example 47 5-Methoxy-N-(2-methyl-2-phenylpropyl)quinazolin-4-amine

Example 47 was prepared from Intermediate 1 and4-chloro-5-methoxyquinazoline (prepared in a similar manner as thepreparation described in Tetrahedron 2004, 60, 5373) in a similar manneras described for the preparation of Example 46. ¹H NMR (400 MHz, CDCl₃)δ ppm 1.45 (s, 6H), 3.55 (s, 3H), 3.88 (d, J=3.52 Hz, 2H), 6.65 (d,J=7.91 Hz, 1H), 7.26-7.36 (m, 2H), 7.41 (t, J=6.81 Hz, 2H), 7.46-7.52(m, 3H), 7.64 (bs, 1H), 8.51 (s, 1H).

Example 484-Chloro-8-methoxy-N-(2-methyl-2-phenylpropyl)isoquinolin-1-amine

Example 48 was prepared from Example 46 in a similar manner as describedfor the preparation of Examples 30 and 31. ¹H NMR (400 MHz, CDCl₃) δ ppm1.36 (s, 6H), 3.51 (s, 3H), 3.72 (d, J=5.27 Hz, 2H), 6.71 (dd, J=6.81,1.98 Hz, 1H), 7.18 (t, J=7.25 Hz, 1H), 7.31 (t, J=7.91 Hz, 2H),7.39-7.46 (m, 4H), 7.80 (s, 1H).

Examples 49 and 508-Chloro-5-methoxy-N-(2-methyl-2-phenylpropyl)quinazolin-4-amine and6-chloro-5-methoxy-N-(2-methyl-2-phenylpropyl)quinazolin-4-amine

Examples 49,8-chloro-5-methoxy-N-(2-methyl-2-phenylpropyl)quinazolin-4-amine [a paleblue solid, less polar compound, ¹H NMR (500 MHz, CDCl₃) δ ppm 1.45 (s,6H), 3.55 (s, 3H), 3.90 (d, J=5.50 Hz, 2H), 6.59 (d, J=8.80 Hz, 1H),7.29 (t, J=7.15 Hz, 1H), 7.42 (t, J=7.70 Hz, 2H), 7.45-7.49 (m, 2H),7.62 (d, J=8.25 Hz, 1H), 7.70 (bs, 1H), 8.64 (s, 1H)], and 50,6-chloro-5-methoxy-N-(2-methyl-2-phenylpropyl)quinazolin-4-amine [awhite solid, more polar compound, ¹H NMR (500 MHz, CDCl₃) δ ppm 1.48 (s,6H) 3.29 (s, 3H) 3.92 (d, J=4.95 Hz, 2H) 7.26-7.29 (m, 1H) 7.41 (t,J=7.70 Hz, 2H) 7.46-7.50 (m, 3H) 7.58 (d, J=8.80 Hz, 1H) 7.67 (bs, 1H)8.53 (s, 1H)], were prepared from Example 47 in a similar manner asdescribed for the preparation of Examples 30 and 31.

Example 512-Chloro-5-methoxy-N-(2-methyl-2-phenylpropyl)quinazolin-4-amine

To a stirred solution of Intermediate 29 (80 mg, 0.35 mmol) in THF (5mL) was added Intermediate 1 (52 mg, 0.35 mmol) followed bytriethylamine (0.12 mL, 0.88 mmol). Upon completion of addition, thereaction mixture was stirred for 1 h. At the conclusions of this period,the volatiles were removed under reduced pressure to provide a residue.The residue was subjected to chromatography on silica gel eluting with 0to 30% EtOAc/hexanes to provide Example 51 as a white solid (82 mg,69%). ¹H NMR (400 MHz, CDCl₃) δ ppm 1.45 (s, 6H), 3.55 (s, 3H), 3.88 (d,J=5.27 Hz, 2H), 6.64 (d, J=7.91 Hz, 1H), 7.23-7.32 (m, 2H), 7.40-7.51(m, 5H), 7.77 (bs, 1H).

Example 525-Methoxy-4-(2-methyl-2-phenylpropylamino)quinazolin-2(1H)-one

To a flask charged with Example 51 (80 mg, 0.23 mmol) was added aceticacid (2 mL). The reaction mixture was heated at 70° C. for 5 h, and thenthe volatiles were removed under reduced pressure to provide a residue.To the residue was added satd NaHCO₃ followed by EtOAc. The organiclayer was separated, washed with brine, dried over Na₂SO₄ and filtered.The volatiles were removed under reduced pressure to provide anotherresidue. This residue was subjected to chromatography on silica geleluting with 0 to 10% MeOH/CH₂Cl₂ to provide Example 52 as a white solid(73 mg, 96%). ¹H NMR (400 MHz, CDCl₃) δ ppm 1.43 (s, 6H), 3.50 (s, 3H),3.98 (d, J=5.27 Hz, 2H), 6.41 (d, J=8.35 Hz, 1H), 6.98 (d, J=8.35 Hz,1H), 7.25-7.35 (m, 2H), 7.40 (t, J=7.25 Hz, 2H), 7.44-7.48 (m, 2H), 7.74(bs, 1H), 11.99 (bs, 1H).

Example 535-Methoxy-1-methyl-4-(2-methyl-2-phenylpropylamino)quinazolin-2(1H)-one

To a stirred solution of Example 52 (32 mg, 0.1 mmol) in DMF (1 mL) wasadded a 60% dispersion of sodium hydride in oil (4 mg, 0.1 mmol). Thereaction mixture was stirred for 10 minutes and then iodomethane (6.2uL, 0.1 mmol) was added. Upon completion of addition the reactionmixture was stirred for 2 h. At the conclusion of this period, thereaction mixture was diluted with EtOAc, washed with brine, dried overNa₂SO₄ and filtered. The volatiles were removed under reduced pressureto provide a residue. The residue was subjected to preparative HPLC(Rt=8.03 minutes using YMC ODS-A 5 u 20×100 mm column with flow rate of20 mL/min over 10 min period; 20 to 100% Solvent B. Solvent A=10/90/0.1%MeOH/H₂O/TFA. Solvent B=90/10/0.1%) to provide Example 53 as a whitesolid (10 mg, 30%). ¹H NMR (500 MHz, CDCl₃) δ ppm 1.41 (s, 6H), 3.50 (s,3H), 3.54 (s, 3H), 3.94 (d, J=4.95 Hz, 2H), 6.49 (d, J=8.25 Hz, 1H),6.76 (d, J=8.25 Hz, 1H), 7.25-7.28 (m, 1H), 7.37-7.45 (m, 5H), 7.71 (bs,1H).

Example 548-Chloro-5-methoxy-4-(2-methyl-2-phenylpropylamino)quinazolin-2(1H)-one

Example 54 was prepared from Example 52 in a similar manner as describedfor the preparation of Examples 30 and 31. ¹H NMR (400 MHz, CDCl₃) δ ppm1.42 (s, 6H), 3.50 (s, 3H), 3.96 (d, J=5.27 Hz, 2H)—, 6.42 (d, J=8.79Hz,1H), 7.25-7.31 (m, 1H), 7.39-7.46 (m, 5H), 7.76 (bs, 1H), 8.26 (bs, 1H).

Example 555-Methoxy-4-(2-methyl-2-phenylpropylamino)-2H-benzo[e][1,3]oxazin-2-one

Compound B: Compound A (prepared in a similar manner as described thepreparation of Example 1, 116 mg, 0.39 mmol) was dissolved in MeOH (10mL) and then palladium (10% on charcoal, 24 mg) was added. The reactionmixture was stirred under H₂ at atmospheric pressure for 16 h. At theconclusion of this period, the reaction mixture was flushed withnitrogen and then filtered through celite. The solvent was removed underreduced pressure to provide Compound B (117 mg) as a gray solid. ¹H NMR(400 MHz, CDCl₃) δ ppm 1.51 (s, 6H), 3.34 (d, J=3.08 Hz, 2H) 3.68 (br-s,3H), 5.95 (d, J=8.35 Hz, 1H), 6.49 (d, J=8.79 Hz, 1H), 7.08 (t, J=8.35Hz, 1H), 7.26 (m, 1H), 7.35-7.45 (m, 4H).

Example 55: Compound B (30 mg, 0.10 mmol) was dissolved in THF (0.4 mL)and then carbonyldiimidizole (“CDI”, 24 mg, 0.15 mmol) was added. Theresulting mixture was heated at 140° C. in a microwave reactor for 5min. After this time, more CDI (0.23 mg, 0.15 mmol) was added and thereaction mixture was heated at 150° C. in a microwave reactor for 5 min.At the conclusion of this period, the reaction mixture was subjected tochromatography on silica gel eluting with 40 to 100% EtOAc/hexanes toprovide Example 55 (19 mg) as a white solid. ¹H NMR (400 MHz, CDCl₃) δppm 1.43 (s, 6H), 3.53 (s, 3H), 3.96 (d, J=5.71 Hz, 2H), 6.58 (d, J=8.35Hz, 1H), 6.86 (d, J=8.79 Hz, 1H), 7.26 (m, 1H), 7.39-7.48 (m, 5H), 7.86(s, 1H), mass spec m/z 325 (M+H).

Examples 56 and 57 Isomers 1 and 2 of3-(3-fluoro-phenyl)-4-(4-methoxy-benzo[d]isoxazol-3-ylamino)-butan-1-ol

Examples 56 and 57 were prepared from 2-fluoro-6-methoxylbenzaldehydeand Intermediate 32 in a similar manner as described for the preparationof Example 1. The enantiomers were separated by preparative-chiral HPLC(CHIRALCEL® OD® 5 cm×50 cm) eluting isocratically with 20%isopropanol/heptane to provide Example 56 (140 mg) and Example 57 (135mg).

Example 58 Isomer 1 of ethyl-carbamic acid3-(3-fluoro-phenyl)-4-(4-methoxy-benzo [d]isoxazol-3-ylamino)-butylester

A solution of Example 56 (20 mg, 0.060 mmol) and ethyl isocyanate(“EtNCO”, 50 μL) in THF (2 ml) was placed in a sealed tube and stirredat 100° C. for 10 h. After this time, the reaction mixture wasconcentrated under reduced pressure to provide an oily residue. The oilyresidue was subjected to column chromatography on silica gel elutingwith 0-100% EtOAc/Hex to provide Example 58 (16.1 mg, 0.040 mmol, 66%)as a colorless oil. [M+H]=402.2.

Example 59 Isomer 2 of ethylcarbamic acid3-(3-fluoro-phenyl)-4-(4-methoxy-benzo [d]isoxazol-3-ylamino)-butylester

Example 59 was prepared from Example 57 in a similar manner as describedfor the preparation of Example 58. [M+H]=402.2.

Example 60(+/−)-4-(4-methoxybenzo[d]isoxazol-3-ylamino)-3-phenylbutan-1-ol

Example 60 were prepared from 2-fluoro-6-methoxylbenzaldehyde andIntermediate 35 in a similar manner as described for the preparation ofExample 1. [M+H]=313.2

Examples 61 and 62 Isomer 1 and Isomer 2 of4-(4-methoxybenzo[d]isoxazol-3-ylamino)-3-phenylbutyl ethylcarbamate

Examples 61 and 62 were prepared from Example 60 in a similar manner asdescribed for the preparation of Example 58. The enantiomers wereseparated by preparative-chiral HPLC (CHIRALCEL® OD® 5 cm×50 cm) elutingisocratically with 35% isopropanol/heptane to provide Example 61 andExample 62. [M+H]=384.2.

Example 63(+/−)-(4-Benzyloxy-2-(3-fluoro-phenyl)-butyl]-(4-methoxy-1-methyl-1H-indazol-3-yl)-amine

Compound C: To a stirred solution of Compound 2 (Intermediate 31, 0.50g, 1.9 mmol) and triethylamaine (“Et₃N”, 0.5 ml) in THF (40 ml) wasadded in one portion both 6-fluoro-2-methoxybenzoic acid (Compounds B,0.38 g, 2.2 mmol) and BOP reagent (1.2 g, 2.2 mmol). Upon completion ofaddition, the resulting solution was stirred at ambient temperature for6 h. After this time, the reaction mixture was concentrated underreduced pressure to provide an oily residue. The oily residue waspurified by silica gel chromatography, eluted with 0-100% EtOAc/Hexaneto provide Compound C (0.41 g, 0.96 mmol, 50%) as a colorless oil.

Compound D: A solution of Compound C (0.41 g, 0.96 mmol) and Lawesson'sreagent (0.23 g, 0.58 mmol) in toluene (10 ml) was stirred at 85° C. for12 h. At the conclusion of this period, the reaction mixture wasconcentrated under reduced pressure to provide an oily residue. The oilyresidue was purified by silica gel chromatography, eluted with 0-80%EtOAc/Hexane to provide Compound D (0.41 g, 96%).

Example 63: A solution of Compound D (45 mg, 0.1 mmol) andmethylhydrazine (0.1 ml) in i-PO (“i-PO”, 1 ml) was stirred at 200° C.under microwave conditions for 0.5 h. At the conclusion of this period,the reaction mixture was concentrated under reduced pressure to providean oily residue. The oily residue was subjected to preparative HPLC (YMCS5 ODS 30×250 mm reverse phase column; 30 min gradient from 70:30 A:B to100% B, where solvent A=90:10:0.1H₂O: MeOH: TFA and solvent B=90:10:0.1MeOH: H₂O: TFA) to provide Example 63 (18.2 mg, 43%). [M+H]=433.0.

Example 64(+/−)-(4-Benzyloxy-2-(3-fluoro-phenyl)-butyl]-(4-methoxy-1H-indazol-3-yl)-amine

A solution of Compound D of Example 63 (45 mg, 0.1 mmol) and hydrazinehydrate (0.2 ml) in isopropyl alcohol (1 ml) of was stirred at 100° C.for 12 h. After this time, the reaction mixture was concentrated underreduced pressure to provide an oily residue. The oily residue wassubjected to preparative HPLC (as described in the preparation ofExample 64) to provide Example 64 (12.2 mg, 28%). [M+H]=419.0.

Example 65(+/−)-(4-Benzyloxy-2-phenyl-butyl)-(4-chloro-1-methyl-1H-pyrazolo[4,3-c]pyridin-3-yl)-amine

Example 65 was prepared in a similar manner as described for thepreparation of Example 63 using 2-chloro-4-fluoronicotinic acid asCompound B. [M+H]=442.1.

Example 66(+/−)-(4-Benzyloxy-2-phenyl-butyl)-(1-methyl-1H-pyrazolo[3,4-b]pyrazin-3-yl)-amine

Example 66 was prepared in a similar manner as described for thepreparation of Example 63 using 3-fluoropyrazine-2-carboxylic acid asCompound B. [M+H]=391.0.

Example 67 4-methoxy-3-(2-methyl-2-phenylpropylamino)-1H-isoindol-1-one

A mixture of 2-methyl-2-phenylpropan-1-amine (Intermediate 1, 500 mg,2.8 mmol) and 3-imino-4-methoxyisoindolin-1-one (Intermediate 38, 430mg, 2.8 mmol) in isopropanol (20 mL) was heated at 70° C. for 4 h, thesolvent was evaporated and the residue was flash chromatographed 0-100%ethyl acetate-hexane to give Example 67 (530 mg, 62%) as a yellow solid.Recrystallization from butyl acetate produced a white solid mp 138-140°C. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.46 (s, 6H), 3.71 (s, 3H), 3.91 (d,J=6.15 Hz, 2H), 6.73 (bs, 1H), 6.92 (d, J=8.35 Hz, 1H), 7.28-7.34 (m,2H), 7.40-7.48 (m, 5H).

Example 685-Methoxy-4-(2-methyl-2-phenylpropylamino)phthalazin-1(2H)-one

A stirred solution of4-methoxy-3-(2-methyl-2-phenylpropylamino)-1H-isoindol-1-one (Example68, 0.40 g, 1.3 mmol) in ethanol (10 mL) was treated with hydrazinehydrate (0.13 mL, 2.6 mmol). After two hours the precipitated solid wasremoved by filtration, the filtrate was concentrated under vacuum, theresidue suspended in ethyl acetate then filtered to give Example 68(0.125 g, 30%) as a tan powder. ¹H NMR (400 MHz, CD₃OD) δ ppm 1.46 (s,6H), 3.64 (s, 2H), 3.68 (s, 3H), 7.28 (t, J=7.25 Hz, 1H), 7.38-7.45 (m,3H), 7.50-7.54 (m, 2H), 7.75-7.84 (bs, 1H), 7.88 (d, J=7.47 Hz, 1H).

Example 694-Chloro-8-methoxy-N-(2-methyl-2-phenylpropyl)phthalazin-1-amine

A mixture of5-methoxy-4-(2-methyl-2-phenylpropylamino)phthalazin-1(2H)-one (Example69, 73 mg, 0.23 mmol) and phosphorus oxychloride (1 mL) was heated in amicrowave reactor at 150° C. for five minutes. The solvent was removedunder vacuum, the residue was partitioned between chloroform and sodiumbicarbonate, the organic fraction was dried over magnesium sulfate andthe solvent was removed under vacuum. The residue was purified by flashchromatography using a 0-100% ethyl acetate-hexane gradient to affordExample 69 (20 mg, 25%) as a white solid. [M+H]/z 342. ¹H NMR (400 MHz,CDCl₃) δ ppm 1.46 (s, 6H), 3.59 (s, 3H), 3.93 (d, J=4.83 Hz, 2H),6.99-7.05 (m, 2H), 7.25-7.30 (m, 1H), 7.41 (t, J=7.69 Hz, 2H), 7.49 (d,J=8.35 Hz, 2H), 7.61-7.64 (m, 2H).

Example 70 4,8-dimethoxy-N-(2-methyl-2-phenylpropyl)phthalazin-1-amine

A mixture of4-chloro-8-methoxy-N-(2-methyl-2-phenylpropyl)phthalazin-1-amine(Example 70, 20 mg, 0.059 mmol) and potassium carbonate (60 mg, 0.43mmol) in methanol (1 mL) was heated in a microwave reactor at a pressurepriority of twenty bar for ten minutes. The solid was filtered off, thesolvent was removed under vacuum and the residue was purified by flashchromatography using 0-100% ethyl acetate-hexane mixture affordingExample 70 (12 mg, 61%) as a tan gum. [M+H]/z 338. ¹H NMR (400 MHz,CDCl₃) δ ppm 1.47 (s, 6H), 3.58 (s, 3H), 3.92 (d, J=5.27 Hz, 2H), 4.10(s, 3H), 6.72 (bs, 1H), 7.24-7.28 (m, 1H), 7.39 (t, J=7.69 Hz, 2H), 7.50(d, J=7.03 Hz, 2H), 7.57-7.64 (m, 2H).

Example 71 8-methoxy-N-(2-methyl-2-phenylpropyl)phthalazin-1-amine

A mixture of4-chloro-8-methoxy-N-(2-methyl-2-phenylpropyl)phthalazin-1-amine(Example 70, 30 mg, 0.088 mmol), ammonium formate (60 mg, 0.95 mmol) and10% palladium on carbon (10 mg) in methanol was heated at 65° C. forthree hours. The catalyst was removed by filtration through a pad ofcelite and the solvent was removed under vacuum. The residue waspartitioned between water and methylene chloride, the organic layer wasdried over magnesium sulfate, the solvent was removed and the productwas purified by flash chromatography using 0-100% ethyl acetate-hexaneto afford Example 71 (11 mg, 41%) asa tan gum. [M+H]/z 308. ¹H NMR (400MHz, CDCl₃) δ ppm 1.48 (s, 6H), 3.59 (s, 3H), 3.98 (d, J=4.83 Hz, 2H),6.97 (d, J=7.91 Hz, 1H), 7.02 (bs, 1H), 7.23-7.32 (m, 2H), 7.40 (t,J=7.69 Hz, 2H), 7.50 (d, J=7.91 Hz, 2H), 7.59 (t, J=7.91 Hz, 1H), 8.71(s, 1H).

Example 725-methoxy-N-(2-methyl-2-phenylpropyl)benzo[e][1,2,3]oxathiazin-2-one-4-amine

A mixture of potassium fluoride (15 mg, 0.25 mmol) and sulfonyldiimidazole (100 mg, 0.51 mmol in DMF (0.5 mL) was heated to 90° C. thena solution of 2-hydroxy-6-methoxy-N-(2-methyl-2-phenylpropyl)benzamidine(Compound B of Example 55, 76 mg, 0.25 mmol} in DMF (0.5 mL) was addedslowly. The temperature was raised to 135° and maintained for two hours.The reaction was cooled, partitioned between chloroform and water, theorganic solution was dried over magnesium sulfate and the solvent wasremoved under vacuum. The residue was purified by flash chromatographyusing 0-100% ethyl acetate-hexane gradient to afford Example 72 (25 mg,25%) as a white solid. [M+H]/z 361. ¹H NMR (400 MHz, CDCl₃) δ ppm 1.44(s, 6H), 3.51 (s, 3H), 3.82 (d, J=5.27 Hz, 2H), 6.69 (d, J=8.35 Hz, 1H),6.86 (d, J=7.91 Hz, 1H), 7.28-7.34 (m, 1H), 7.40-7.48 (m, 5H), 7.93 (bs,1H).

Publications and references, including but not limited to patents andpatent applications, cited in this specification are herein incorporatedby reference in their entirety in the entire portion cited as if eachindividual publication or reference were specifically and individuallyindicated to be incorporated by reference herein as being fully setforth. Any patent application to which this application claims priorityis also incorporated by reference herein in the manner described abovefor publications and references.

While this invention has been described with an emphasis upon particularembodiments, it will be obvious to those of ordinary skill in the artthat variations in the particular compounds and methods may be used andthat it is intended that the invention may be practiced otherwise thanas specifically described herein. Accordingly, this invention includesall modifications encompassed within the spirit and scope of theinvention as defined by the claims that follow.

1. A compound of formula I

or a stereoisomer or a tautomer or a pharmaceutically acceptable saltthereof, wherein: R¹ is an aryl or heterocyclic ring, which may beoptionally substituted with one or more R¹⁰'s; R² and R³ areindependently: (a) halo, (b) (C₁-C₆)-alkoxy optionally substituted withone or more R¹¹'s, (c) (C₁-C₄)-perfluoroalkyl, (d)(C₁-C₆)-alkyl-S(O)_(n)—, (e) aryl-(CH₂)_(r)—S(O)_(n)—, (f) cyano, (g)—CO₂H, (h) —CO(C₁-C₆)-alkyl, (i) —CO₂(C₁-C₆)-alkyl, (j) —CONR⁸R⁹, (k)—O(CO)NR⁸R⁹, (l) —NR⁸(CO)NR⁸R⁹, (m) —NR⁸R⁹, (n) hydrogen, (o)C₁-C₁₀-alkyl optionally substituted with one or more R¹¹'s, (p)(C₂-C₁₀)-alkenyl optionally substituted with one or more R¹¹'s, (q)(C₂-C₁₀)-alkynyl optionally substituted with one or more R¹¹'s, (r) aryloptionally substituted with one or more R¹¹'s, (s) heterocyclyloptionally substituted with one or more R¹¹'s, or (t) —NR⁸(CO)OR²¹,provided that both R² and R³ are not simultaneously hydrogen; R⁴ is: (a)hydrogen, (b) C₁-C₁₀-alkyl, (c) —CO(C₁-C₆)-alkyl, (d) —COaryl, (e)—COheterocyclyl, (f) —CO₂(C₁-C₆)-alkyl, (g) —CO₂aryl, (h)—CO₂heterocyclyl, (i) —CONR⁸R⁹, (j) —S(O)_(n)-alkyl, (k) —S(O)_(n)-aryl,(l) —S(O)_(n)-heterocyclyl, or (m) —S(O)_(n)—NR⁸R⁹; R⁵ is

wherein the dashed line(s) represent an optional double bond; T is O, S,C═O, N, NR¹⁹ or C(R²⁰)_(p); Q, X, U, V and W are independently O, S,C═O, N, NR¹⁹ or C(R²⁰)_(p), provided that Q is not C(R²⁰)_(p) when X isN or NR¹⁹; R⁸ and R⁹ are independently: (a) hydrogen, (b)—[(C═O)O_(r)]_(s)aryl, wherein the aryl may be optionally substitutedwith one or more R¹⁴'s, (c) —[(C═O)O_(r)]_(s)(C₂-C₈)-alkenyl, whereinthe alkenyl may be optionally substituted with one or more R¹⁴'s, (d)—[(C═O)O_(r)]_(s)(C₁-C₈)alkyl, wherein the alkyl may be optionallysubstituted with one or more R¹⁴'s, (e) —S(O)_(p)(C₁-C₈)alkyl, whereinthe alkyl may be optionally substituted with one or more R¹⁴'s, (f)—S(O)_(p)NR¹⁶R¹⁷, (g) —C(═NR¹⁸)(NR¹⁶R¹⁷), or (h) heterocyclyl optionallysubstituted with one or more R¹⁴'s, or R⁸ and R⁹ are taken together withthe nitrogen to which both are attached to form a 3- to 8-membered ring,which may optionally contain 1-4 heteroatoms selected from N, O, and Sand be optionally substituted with one or more R¹⁴'s; R¹⁰ is: (a) halo,(b) —OH, (c) —O[(C═O)O_(r)]_(s)(C₁-C₆)-alkyl, (d)—O[(C═O)O_(r)]_(s)(C₂-C₆)-alkenyl, (e) —O[(C═O)O_(r)]_(s)aryl, (f)—O[(C═O)O_(r)]_(s)heteroaryl, (g) (C₁-C₆)-alkyl-S(O)_(n)—, (h)aryl-(C₁-C₆)alkyloxy-, (i) cyano, (j) nitro, (k) —NR⁸R⁹, (l)—O(CO)NR⁸R⁹, (m) —CHO, (n) —COOH, (o) —CO(C₁-C₆)-alkyl, (p)—CO₂(C₁-C₆)-alkyl, (q) —CONR⁸R⁹, (r) aryl, which may optionally besubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, 4)(C₁-C₄)-perfluoroalkyl, 5) (C₂-C₆)-alkenyl, 6) (C₂-C₆)-alkynyl, 7)(C₁-C₆)-alkyloxy, 8) (C₁-C₆)-alkyl-S(O)_(n)—, 9) cyano, 10) —COOH, 11)—CO(C₁-C₆)-alkyl, 12) —CO₂(C₁-C₆)-alkyl, 13) —CONR⁸R⁹, 14) —NR⁸R⁹, 15)—O(C═O)—(C₁-C₆)-alkyl, and 16) —O(C═O)NR⁸R⁹, (s) heteroaryl optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, 4)(C₁-C₄)-perfluoroalkyl, 5) (C₂-C₆)-alkenyl, 6) (C₂-C₆)-alkynyl, 7)(C₁-C₆)-alkyloxy, 8) (C₁-C₆)-alkyl-S(O)_(n)—, 9) cyano, 10) —COOH, 11)—CO(C₁-C₆)-alkyl, 12) —CO₂(C₁-C₆)-alkyl, 13) —CONR⁸R⁹, 14) —NR⁸R⁹, 15)—O(C═O)—(C₁-C₆)-alkyl, and 16) —O(C═O)NR⁸R⁹, (t) heterocyclo other thanheteroaryl which is optionally substituted with one or more substituentsselected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, 4) (C₁-C₄)-perfluoroalkyl, 5) (C₂-C₆)-alkenyl, 6)(C₂-C₆)-alkynyl, 7) (C₁-C₆)-alkyloxy, 8) (C₁-C₆)-alkyl-S(O)_(n)—, 9)cyano, 10) —COOH, 11) —CO(C₁-C₆)-alkyl, 12) —CO₂(C₁-C₆)-alkyl, 13)—CONR⁸R⁹, 14) —NR⁸R⁹, 15) —O(C═O)—(C₁-C₆)-alkyl, and 16) —O(C═O)NR⁸R⁹,(u) benzyl-S(O)_(n)—, (v) (C₂-C₁₀)-alkenyl, which may optionally besubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) cyano, 6) —COOH, 7) —CO(C₁-C₆)-alkyl, 8)—CO₂(C₁-C₆)-alkyl, 9) —CONR⁸R⁹, 10) —NR⁸R⁹, 11) —O(C═O)—(C₁-C₆)-alkyl,and 12) —O(C═O)NR⁸R⁹, (w) (C₂-C₁₀)-alkynyl wherein alkynyl is optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) cyano, 6) —COOH, 7) —CO(C₁-C₆)-alkyl, 8)—CO₂(C₁-C₆)-alkyl, 9) —CONR⁸R⁹, 10) —NR⁸R⁹, 11) —O(C═O)—(C₁-C₆)-alkyl,and 12) —O(C═O)NR⁸R⁹, (x) —(C₁-C₁₀)-alkyl, which may optionally besubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) benzyl-S(O)_(n)—, 6) cyano, 7) —COOH, 8)—CO(C₁-C₆)-alkyl, 9) —CO₂(C₁-C₆)-alkyl, 10) —CONR⁸R⁹, 11) —NR⁸R⁹, 12)—O(C═O)—(C₁-C₆)-alkyl, and 13) —O(C═O)NR⁸R⁹; R¹¹ is: (a) halo, (b) —OH,(c) —O[(C═O)O_(r)]_(s)(C₁-C₆)-alkyl, (d)—O[(C═O)O_(r)]_(s)(C₂-C₆)-alkenyl, (e) —O[(C═O)O_(r)]_(s)aryl, (f)—O[(C═O)O_(r)]_(s)heteroaryl, (g) (C₁-C₆)-alkyl-S(O)_(n)—, (h)aryl-(C₁-C₆)alkyloxy-, (i) cyano, (j) —NR⁸R⁹, (k) —O(CO)NR⁸R⁹, (l)—COOH, (m) —CO(C₁-C₆)-alkyl, (n) —CO₂(C₁-C₆)-alkyl, (o) —CONR⁸R⁹, (p)aryl, which may optionally be substituted with one or more substituentsselected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, 4) aryl-(C₁-C₆)alkyloxy-, 5) (C₁-C₄)-perfluoroalkyl, 6)(C₂-C₆)-alkenyl, 7) (C₂-C₆)-alkynyl, 8) (C₁-C₆)-alkyloxy, 9)(C₁-C₆)-alkyl-S(O)_(n)—, 10) cyano, 11) —COOH, 12) —CO(C₁-C₆)-alkyl, 13)—CO₂(C₁-C₆)-alkyl, 14) —CONR⁸R⁹, 15) —NR⁸R⁹, 16) —O(C═O)—(C₁-C₆)-alkyl,and 17) —O(C═O)NR⁸R⁹, (q) heteroaryl optionally substituted with one ormore substituents selected from the group consisting of: 1) halo, 2)—OH, 3) (C₁-C₆)-alkyl, 4) aryl-(C₁-C₆)alkyloxy-, 5)(C₁-C₄)-perfluoroalkyl, 6) (C₂-C₆)-alkenyl, 7) (C₂-C₆)-alkynyl, 8)(C₁-C₆)-alkyloxy, 9) (cl-C₆)-alkyl-S(O)_(n)—, 10) cyano, 11) —COOH, 12)—CO(C₁-C₆)-alkyl, 13) —CO₂(C₁-C₆)-alkyl, 14) —CONR⁸R⁹, 15) —NR⁸R⁹, 16)—O(C═O)—(C₁-C₆)-alkyl, and 17) —O(C═O)NR⁸R⁹, (r) heterocyclo other thanheteroaryl which is optionally substituted with one or more substituentsselected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, 4) aryl-(C₁-C₆)alkyloxy-, 5) (C₁-C₄)-perfluoroalkyl, 6)(C₂-C₆)-alkenyl, 7) (C₂-C₆)-alkynyl, 8) (C₁-C₆)-alkyloxy, 9)(C₁-C₆)-alkyl-S(O)_(n)—, 10) cyano, 11) —COOH, 12) —CO(C₁-C₆)-alkyl, 13)—CO₂(C₁-C₆)-alkyl, 14) —CONR⁸R⁹, 15) —NR⁸R⁹, 16) —O(C═O)—(C₁-C₆)-alkyl,and 17) —O(C═O)NR⁸R⁹, (s) —(C₂-C₁₀)-alkenyl, which may optionally besubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) phenyl-(C₁-C₆)-alkyloxy-, 6) cyano, 7) —CHO,8) —COOH, 9) —CO(C₁-C₆)-alkyl, 10) —CO₂(C₁-C₆)-alkyl, 11) —CONR⁸R⁹, 12)—NR⁸R⁹, 13) aryl, 14) heteroaryl as defined above, 15) heterocyclo otherthan heteroaryl as defined above, 16) —O(C═O)—(C₁-C₆)-alkyl, and 17)—O(C═O)NR⁸R⁹, (t) (C₂-C₁₀)-alkynyl wherein alkynyl is optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) phenyl-(C₁-C₆)-alkyloxy-, 6) cyano, 7)vinyl, 8) —CHO, 9) —COOH, 10) —CO(C₁-C₆)-alkyl, 11) —CO₂(C₁-C₆)-alkyl,12) —CONR⁸R⁹, 13) —NR⁸R⁹, 14) aryl, wherein aryl is defined as above,15) heteroaryl as defined above, 16) heterocyclyl other than heteroarylas defined above, 17) —O(C═O)—(C₁-C₆)-alkyl, and 18) —O(C═O)NR⁸R⁹, (u)—(C₁-C₁₀)-alkyl, which may optionally be substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyloxy, 4) (C₁-C₆)-alkyl-S(O)_(n)—, 5) benzyl-S(O)_(n)—, 6)cyano, 7) —COOH, 8) —CO(C₁-C₆)-alkyl, 9) —CO₂(C₁-C₆)-alkyl, 10)—CONR⁸R⁹, 11) —NR⁸R⁹, 12) —O(C═O)—(C₁-C₆)-alkyl, and 13) —O(C═O)NR⁸R⁹,(v) —O(CH₂)_(m)-heteroaryl as defined above; R¹² is: (a) halo, (b) —OH,(c) —O[(C═O)O_(r)]_(s)(C₁-C₆)-alkyl, (d)—O[(C═O)O_(r)]_(s)(C₂-C₆)-alkenyl, (e) —O[(C═O)O_(r)]_(s)aryl, (f)—O[(C═O)O_(r)]₅heteroaryl, (g) (C₁-C₆)-alkyl-S(O)_(n)—, (h)aryl-(C₁-C₆)alkyloxy-, (i) cyano, (j) nitro, (k) —NR⁸R⁹, (l)—O(CO)NR⁸R⁹, (m) —CHO, (n) —COOH, (o) —CO(C₁-C₆)-alkyl, (p)—CO₂(C₁-C₆)-alkyl, (q) —CONR⁸R⁹, (r) aryl, which may optionally besubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)alkyl, 4)(C₁-C₄)-perfluoroalkyl, 5) (C₂-C₆)-alkenyl, 6) (C₂-C₆)-alkynyl, 7)(C₁-C₆)-alkyloxy, 8) (C₁-C₆)-alkyl-S(O)_(n)—, 9) cyano, 10) —COOH, 11)—CO(C₁-C₆)-alkyl, 12) —CO₂(C₁-C₆)-alkyl, 13) —CONR⁸R⁹, 14) —NR⁸R⁹, 15)—O(C═O)—(C₁-C₆)-alkyl, and 16) —O(C═O)NR⁸R⁹, (s) heteroaryl optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, 4)(C₁-C₄)-perfluoroalkyl, 5) (C₂-C₆)-alkenyl, 6) (C₂-C₆)-alkynyl, 7)(C₁-C₆)-alkyloxy, 8) (C₁-C₆)-alkyl-S(O)_(n)—, 9) cyano, 10) —COOH, 11)—CO(C₁-C₆)-alkyl, 12) —CO₂(C₁-C₆)-alkyl, 13) —CONR⁸R⁹, 14) —NR⁸R⁹, 15)—O(C═O)—(C₁-C₆)-alkyl, and 16) —O(C═O)NR⁸R⁹, (t) heterocyclo other thanheteroaryl which is optionally substituted with one or more substituentsselected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, 4) (C₁-C₄)-perfluoroalkyl, 5) (C₂-C₆)-alkenyl, 6)(C₂-C₆)-alkynyl, 7) (C₁-C₆)-alkyloxy, 8) (C₁-C₆)-alkyl-S(O)_(n)—, 9)cyano, 10) —COOH, 11) —CO(C₁-C₆)-alkyl, 12) —CO₂(C₁-C₆)-alkyl, 13)—CONR⁸R⁹, 14) —NR⁸R⁹, 15) —O(C═O)—(C₁-C₆)-alkyl, and 16) —O(C═O)NR⁸R⁹,(u) benzyl-S(O)_(n)—, (v) (C₂-C₁₀)-alkenyl, which may optionally besubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) cyano, 6) —COOH, 7) —CO(C₁-C₆)-alkyl, 8)—CO₂(C₁-C₆)-alkyl, 9) —CONR⁸R⁹, 10) —NR⁸R⁹, 11) —O(C═O)—(C₁-C₆)-alkyl,and 12) —O(C═O)NR⁸R⁹, (w) (C₂-C₁₀)-alkynyl wherein alkynyl is optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) cyano, 6) —COOH, 7) —O(C₁-C₆)-alkyl, 8)—CO₂(C₁-C₆)-alkyl, 9) —CONR⁸R⁹, 10) —NR⁸R⁹, 11) —O(C═O)—(C₁-C₆)-alkyl,and 12) —O(C═O)NR⁸R⁹, (x) —(C₁-C₁₀)-alkyl, which may optionally besubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) benzyl-S(O)_(n)—, 6) cyano, 7) —COOH, 8)—CO(C₁-C₆)-alkyl, 9) —CO₂(C₁-C₆)-alkyl, 10) —CONR⁸R⁹, 11) —NR⁸R⁹, 12)—O(C═O)—(C₁-C₆)-alkyl, and 13) —O(C═O)NR⁸R⁹, (y) ═O; R¹⁴ is: (a) halo,(b) —OH, (c) —O[(C═O)O_(r)]_(s)(C₁-C₆)-alkyl, (d)—O[(C═O)O_(r)]_(s)(C₂-C₆)-alkenyl, (e) —O[(C═O)O_(r)]_(s)aryl, (f)—O[(C═O)O_(r)]_(s)heteroaryl, (g) (C₁-C₆)-alkyl-S(O)_(n)—, (h)aryl-(C₁-C₆)alkyloxy-, (i) cyano, (j) nitro, (k) —NR⁸R⁹, (l)—O(CO)NR⁸R⁹, (m) —CHO, (n) —COOH, (o) —CO(C₁-C₆)-alkyl, (p)—CO₂(C₁-C₆)-alkyl, (q) —CONR⁸R⁹, (r) aryl, which may optionally besubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, 4)(C₁-C₄)-perfluoroalkyl, 5) (C₂-C₆)-alkenyl, 6) (C₂-C₆)-alkynyl, 7)(C₁-C₆)-alkyloxy, 8) (C₁-C₆)-alkyl-S(O)_(n)—, 9) cyano, 10) —COOH, 11)—CO(C₁-C₆)-alkyl, 12) —CO₂(C₁-C₆)-alkyl, 13) —CONR⁸R⁹, 14) —NR⁸R⁹, 15)—O(C═O)—(C₁-C₆)-alkyl, and 16) —O(C═O)NR⁸R⁹, (s) heteroaryl optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, 4)(C₁-C₄)-perfluoroalkyl, 5) (C₂-C₆)-alkenyl, 6) (C₂-C₆)-alkynyl, 7)(C₁-C₆)-alkyloxy, 8) (C₁-C₆)-alkyl-S(O)_(n)—, 9) cyano, 10) —COOH, 11)—CO(C₁-C₆)-alkyl, 12) —CO₂(C₁-C₆)-alkyl, 13) —CONR⁸R⁹, 14) —NR⁸R⁹, 15)—O(C═O)—(C₁-C₆)-alkyl, and 16) —O(C═O)NR⁸R⁹, (t) heterocyclo other thanheteroaryl which is optionally substituted with one or more substituentsselected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, 4) (C₁-C₄)-perfluoroalkyl, 5) (C₂-C₆)-alkenyl, 6)(C₂-C₆)-alkynyl, 7) (C₁-C₆)-alkyloxy, 8) (C₁-C₆)-alkyl-S(O)_(n)—, 9)cyano, 10) —COOH, 11) —CO(C₁-C₆)-alkyl, 12) —CO₂(C₁-C₆)-alkyl, 13)—CONR⁸R⁹, 14) —NR⁸R⁹, 15) —O(C═O)—(C₁-C₆)-alkyl, and 16) —O(C═O)NR⁸R⁹,(u) benzyl-S(O)_(n)—, (v) (C₂-C₁₀)-alkenyl, which may optionally besubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) cyano, 6) —COOH, 7) —CO(C₁-C₆)-alkyl, 8)—CO₂(C₁-C₆)-alkyl, 9) —CONR⁸R⁹, 10) —NR⁸R⁹, 11) —O(C═O)—(C₁-C₆)-alkyl,and 12) —O(C═O)NR⁸R⁹, (w) (C₂-C₁₀)-alkynyl wherein alkynyl is optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) cyano, 6) —COOH, 7) —CO(C₁-C₆)-alkyl, 8)—CO₂(C₁-C₆)-alkyl, 9) —CONR⁸R⁹, 10) —NR⁸R⁹, 11) —O(C═O)—(C₁-C₆)-alkyl,and 12) —O(C═O)NR⁸R⁹, (x) —(C₁-C₁₀)-alkyl, which may optionally besubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) benzyl-S(O)_(n)—, 6) cyano, 7) —COOH, 8)—CO(C₁-C₆)-alkyl, 9) —CO₂(C₁-C₆)-alkyl, 10) —CONR⁸R⁹, 11) —NR⁸R⁹, 12)—O(C═O)—(C₁-C₆)-alkyl, and 13) —O(C═O)NR⁸R⁹; R¹⁶ and R¹⁷ areindependently: (a) aryl, which may optionally be substituted with one ormore substituents selected from the group consisting of: 1) halo, 2)—OH, 3) (C₁-C₆)-alkyl, 4) (C₁-C₄)-perfluoroalkyl, 5) (C₂-C₆)-alkenyl, 6)(C₂-C₆)-alkynyl, 7) (C₁-C₆)-alkyloxy, 8) (C₁-C₆)-alkyl-S(O)_(n)—, 9)cyano, 10) —COOH, 11) —CO(C₁-C₆)-alkyl, 12) —CO₂(C₁-C₆)-alkyl, 13)—CONR⁸R⁹, 14) —NR⁸R⁹, 15) —O(C═O)—(C₁-C₆)-alkyl, and 16) —O(C═O)NR⁸R⁹,(b) heteroaryl optionally substituted with one or more substituentsselected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, 4) (C₁-C₄)-perfluoroalkyl, 5) (C₂-C₆)-alkenyl, 6)(C₂-C₆)-alkynyl, 7) (C₁-C₆)-alkyloxy, 8) (C₁-C₆)-alkyl-S(O)_(n)—, 9)cyano, 10) —COOH, 11) —CO(C₁-C₆)-alkyl, 12) —CO₂(C₁-C₆)-alkyl, 13)—CONR⁸R⁹, 14) —NR⁸R⁹, 15) —O(C═O)—(C₁-C₆)-alkyl, and 16) —O(C═O)NR⁸R⁹,(c) heterocyclo other than heteroaryl which is optionally substitutedwith one or more substituents selected from the group consisting of: 1)halo, 2) —OH, 3) (C₁-C₆)-alkyl, 4) (C₁-C₄)-perfluoroalkyl, 5)(C₂-C₆)-alkenyl, 6) (C₂-C₆)-alkynyl, 7) (C₁-C₆)-alkyloxy, 8)(C₁-C₆)-alkyl-S(O)_(n)—, 9) cyano, 10) —COOH, 11) —CO(C₁-C₆)-alkyl, 12)—CO₂(C₁-C₆)-alkyl, 13) —CONR⁸R⁹, 14) —NR⁸R⁹, 15) —O(C═O)—(C₁-C₆)-alkyl,and 16) —O(C═O)NR⁸R⁹, (d) (C₂-C₁₀)-alkenyl, which may optionally besubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) cyano, 6) —COOH, 7) —CO(C₁-C₆)-alkyl, 8)—CO₂(C₁-C₆)-alkyl, 9) —CONR⁸R⁹, 10) —NR⁸R⁹, 11) —O(C═O)—(C₁-C₆)-alkyl,and 12) —O(C═O)NR⁸R⁹, (e) (C₂-C₁₀)-alkynyl wherein alkynyl is optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) cyano, 6) —COOH, 7) —CO(C₁-C₆)-alkyl, 8)—CO₂(C₁-C₆)-alkyl, 9) —CONR⁸R⁹, 10) —NR⁸R⁹, 11) —O(C═O)—(C₁-C₆)-alkyl,and 12) —O(C═O)NR⁸R⁹, (f) —(C₁-C₁₀)-alkyl, which may optionally besubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) benzyl-S(O)_(n)—, 6) cyano, 7) —COOH, 8)—CO(C₁-C₆)-alkyl, 9) —CO₂(C₁-C₆)-alkyl, 10) —CONR⁸R⁹, 11) —NR⁸R⁹, 12)—O(C═O)—(C₁-C₆)-alkyl, and 13) —O(C═O)NR⁸R⁹, or R¹⁶ and R¹⁷ are takentogether with the nitrogen to which both are attached to form a 3- to8-membered ring, which may optionally contain 1-4 heteroatoms selectedfrom N, O, and S and be optionally substituted with one or more R¹⁴'s;R¹⁸ is cyano, —COR¹⁶ or —SO₂R¹⁶; R¹⁹ is: (a) hydrogen, (b)(C₁-C₆)-alkyl, (c) —CO(C₁-C₆)-alkyl, (d) —CO(C₁-C₆)-aryl, (e)—CO(C₁-C₆)-heteroaryl, (f) —CO₂(C₁-C₆)-alkyl, (g) CO₂(C₁-C₆)-aryl, (h)CO₂(C₁-C₆)-heteroaryl, (i) —CONR⁸R⁹, (j) —S(O)_(n)-alkyl, (k)—S(O)_(n)-aryl, (l) —S(O)_(n)-heteroaryl, or (m) —S(O)_(n)—NR⁸R⁹; R²⁰ isindependently: (a) hydrogen, (b) halo, (c) —OH, (d)—O[(C═O)O_(r)]_(s)(C₁-C₆)-alkyl, (e) —O[(C═O)O_(r)]_(s)(C₂-C₆)-alkenyl,(f) —O[(C═O)O_(r)]_(s)aryl, (g) —O[(C═O)O_(r)]_(s)heteroaryl, (h)(C₁-C₆)-alkyl-S(O)_(n)—, (i) aryl-(C₁-C₆)alkyloxy-, (j) cyano, (k)nitro, (l) —NR⁸R⁹, (m) —O(CO)NR⁸R⁹, (n) —CHO, (o) COOH, (p)—CO(C₁-C₆)-alkyl, (q) —CO₂(C₁-C₆)-alkyl, (r) —CONR⁸R⁹, (s) aryl, whichmay optionally be substituted with one or more substituents selectedfrom the group consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, 4)(C₁-C₄)-perfluoroalkyl, 5) (C₂-C₆)-alkenyl, 6) (C₂-C₆)-alkynyl, 7)(C₁-C₆)-alkyloxy, 8) (C₁-C₆)-alkyl-S(O)_(n)—, 9) cyano, 10) —COOH, 11)—O(C₁-C₆)-alkyl, 12) —CO₂(C₁-C₆)-alkyl, 13) —CONR⁸R⁹, 14) —NR⁸R⁹, 15)—O(C═O)—(C₁-C₆)-alkyl, and 16) —O(C═O)NR⁸R⁹, (t) heteroaryl optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, 4)(C₁-C₄)-perfluoroalkyl, 5) (C₂-C₆)-alkenyl, 6) (C₂-C₆)-alkynyl, 7)(C₁-C₆)-alkyloxy, 8) (C₁-C₆)-alkyl-S(O)_(n)—, 9) cyano, 10) —COOH, 11)—CO(C₁-C₆)-alkyl, 12) —CO₂(C₁-C₆)-alkyl, 13) —CONR⁸R⁹, 14) —NR⁸R⁹, 15)—O(C═O)—(C₁-C₆)-alkyl, and 16) —O(C═O)NR⁸R⁹, (u) heterocyclo other thanheteroaryl which is optionally substituted with one or more substituentsselected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, 4) (C₁-C₄)-perfluoroalkyl, 5) (C₂-C₆)-alkenyl, 6)(C₂-C₆)-alkynyl, 7) (C₁-C₆)-alkyloxy, 8) (C₁-C₆)-alkyl-S(O)_(n)—, 9)cyano, 10) —COOH, 11) —CO(C₁-C₆)-alkyl, 12) —CO₂(C₁-C₆)-alkyl, 13)—CONR⁸R⁹, 14) —NR⁸R⁹, 15) —O(C═O)—(C₁-C₆)-alkyl, and 16) —O(C═O)NR⁸R⁹,(v) benzyl-S(O)_(n)—, (w) (C₂-C₁₀)-alkenyl, which may optionally besubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) cyano, 6) —COOH, 7) —CO(C₁-C₆)-alkyl, 8)—CO₂(C₁-C₆)-alkyl, 9) —CONR⁸R⁹, 10) —NR⁸R⁹, 11) —O(C═O)—(C₁-C₆)-alkyl,and 12) —O(C═O)NR⁸R⁹, (x) (C₂-C₁₀)-alkynyl wherein alkynyl is optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) cyano, 6) —COOH, 7) —CO(C₁-C₆)-alkyl, 8)—CO₂(C₁-C₆)-alkyl, 9) —CONR⁸R⁹, 10) —NR⁸R⁹, 11) —O(C═O)—(C₁-C₆)-alkyl,and 12) —O(C═O)NR⁸R⁹, (y) —(C₁-C₁₀)-alkyl, which may optionally besubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) benzyl-S(O)_(n)—, 6) cyano, 7) —COOH, 8)—CO(C₁-C₆)-alkyl, 9) —CO₂(C₁-C₆)-alkyl, 10) —CONR⁸R⁹, 11) —NR⁸R⁹, 12)—O(C═O)—(C₁-C₆)-alkyl, and 13) —O(C═O)NR⁸R⁹; R²¹ is: (a) C₁-C₁₀-alkyloptionally substituted with one or more R¹¹'s, (b) C₃-C₈-cycloalkyloptionally substituted with one or more R¹¹'s, (c) aryl optionallysubstituted with one or more R¹¹'s, or (d) heterocyclyl optionallysubstituted with one or more R¹¹'s; m is 1 to 5; n is 0 to 3; p is 1 or2; r is 0 to 5; and s is 0 to 4; with the following provisos: a)excluding compounds wherein: R¹ is phenyl, which may be optionallysubstituted with one or more R¹⁰'s; one of R² or R³ is hydrogen and theother R² or R³ is C₁-C₇-alkyl; R⁴ is hydrogen; R⁵ is

 and R¹² is —NR⁸R⁹, wherein R⁸ is hydrogen; and R⁹ is phenyl orphenylalkyl, wherein the phenyl may be optionally substituted with halo,(C₁-C₆)-alkyl, perfluoromethyl, (C₁-C₆)-alkyloxy, cyano,—CO₂(C₁-C₆)-alkyl, or —CONR⁸R⁹, wherein R⁸ is H and R⁹ is H or(C₁-C₇)alkyl; and b) excluding compounds wherein: R¹ is aryl or pyridyl,which may be optionally substituted with one or more R¹⁰'s; one R² or R³is hydrogen and the other R² or R³ is C₁-C₄-alkyl or both R² and R³ areC₁-C₄-alkyl; R⁴ is H; R⁵ is

 which may be optionally substituted with one or more R¹³'s; and R²⁰contains an optionally substituted 4-pyridinylalkylene moiety, anoptionally substituted 4-pyrimidinylalkylene moiety, or an optionallysubstituted 4-triazinylalkylene moiety.
 2. The compound of claim 1,wherein R¹ is a monocylic aryl ring, which may be optionally substitutedwith one or more R¹⁰'s.
 3. The compound of claim 1, wherein R¹ is amonocylic heterocyclic ring, which may be optionally substituted withone or more R¹⁰'s.
 4. The compound of claim 1, wherein R⁵ is


5. The compound of claim 4, wherein R⁵ is


6. The compound of claim 4, wherein T is O, S, C═O, NR¹⁹ or CR²⁰; and U,V, and W are C(R²⁰)_(p).
 7. The compound of claim 6, wherein T is O, S,C═O or NR¹⁹.
 8. The compound of claim 1, wherein R¹ is

and both Q and X are not C═O.
 9. The compound of claim 8, wherein U, V,and W are (CR²⁰)_(p).
 10. The compound of claim 9, wherein Q is C═O andX is O, N or NR¹⁹.
 11. The compound of claim 8, wherein Q is O or NR¹⁹and X is C═O.
 12. The compound of claim 1, wherein: R¹ is an aryl orheterocyclic ring, which may be optionally substituted with one or moreR¹⁰'s; R² and R³ are independently: (a) halo, (b) (C₁-C₆)-alkoxyoptionally substituted with one or more R¹¹'s, (c)(C₁-C₄)-perfluoroalkyl, (d) —CO(C₁-C₆)-alkyl, (e) —CO₂(C₁-C₆)-alkyl, (f)—CONR⁸R⁹, (g) —O(CO)NR⁸R⁹, (h) —NR⁸(CO)NR⁸R⁹, (i) —NR⁸R⁹, (j) hydrogen,(k) C₁-C₁₀-alkyl optionally substituted with one or more R¹¹'s, (l) aryloptionally substituted with one or more R¹¹'s, (m) heterocyclyloptionally substituted with one or more R¹¹'s, or (n) —NR(CO)OR²¹,provided that both R² and R³ are not simultaneously hydrogen; R⁴ is: (a)hydrogen, (b) C₁-C₁₀-alkyl, (c) —CO(C₁-C₆)-alkyl, (d) —COaryl, (e)—COheterocyclyl, (f) —CO₂(C₁-C₆)-alkyl, (g) CO₂aryl, or (h)CO₂heterocyclyl; R⁵ is

Q is a O, C═O, N, NR¹⁹ or C(R²⁰)_(p); T is O, S, C═O, N, NR¹⁹ orC(R²⁰)_(p); X, U, V and W are independently O, C═O or C(R²⁰)_(p); R⁸ andR⁹ are independently: (a) hydrogen, (b) —[(C═O)O_(r)]_(s)aryl, whereinthe aryl may be optionally substituted with one or more R¹⁴'s, (c)—[(C═O)O_(r)]_(s)(C₂-C₈)-alkenyl, wherein the alkenyl may be optionallysubstituted with one or more R¹⁴'s, (d) —[(C═O)O_(r)]_(s)(C₁-C₈)alkyl,wherein the alkyl may be optionally substituted with one or more R¹⁴'s,(e) —S(O)_(p)(C₁-C₈)alkyl, wherein the alkyl may be optionallysubstituted with one or more R¹⁴'s, (f) heterocyclyl optionallysubstituted with one or more R¹⁴'s; R¹⁰ is: (a) halo, (b) —OH, (c)—O[(C═O)O_(r)]_(s)(C₁-C₆)-alkyl, (d) —O[(C═O)O_(r)]_(s)(C₂-C₆)-alkenyl,(e) —O[(C═O)O_(r)]_(s)aryl, (f) —O[(C═O)O_(r)]_(s)heteroaryl, (g) cyano,(h) nitro, (i) —NR⁸R⁹, (l) —O(CO)NR⁸R⁹, (k) —CO(C₁-C₆)-alkyl, (l)—CO₂(C₁-C₆)-alkyl, (m) —CONR⁸R⁹, (n) aryl, which may optionally besubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, 4)(C₁-C₄)-perfluoroalkyl, 5) (C₁-C₆)-alkyloxy, 6) cyano, 7)—CO(C₁-C₆)-alkyl, 8) —CO₂(C₁-C₆)-alkyl, 9) —CONR⁸R⁹, 10) —NR⁸R⁹, 11)—O(C═O)—(C₁-C₆)-alkyl, and 12) —O(C═O)NR⁸R⁹, (o) heteroaryl optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, 4)(C₁-C₄)-perfluoroalkyl, 5) (C₁-C₆)-alkyloxy, 6) cyano, 7)—CO(C₁-C₆)-alkyl, 8) —CO₂(C₁-C₆)-alkyl, 9) —CONR⁸R⁹, 10) —NR⁸R⁹, 11)—O(C═O)—(C₁-C₆)-alkyl, and 12) —O(C═O)NR⁸R⁹, (p) heterocyclo other thanheteroaryl which is optionally substituted with one or more substituentsselected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, 4) (C₁-C₄)-perfluoroalkyl, 5) (C₁-C₆)-alkyloxy, 6) cyano,7) —CO(C₁-C₆)-alkyl, 8) —CO₂(C₁-C₆)-alkyl, 9) —CONR⁸R⁹, 10) —NR⁸R⁹, 11)—O(C═O)—(C₁-C₆)-alkyl, and 12) —O(C═O)NR⁸R⁹, (c) —(C₁-C₁₀)-alkyl, whichmay optionally be substituted with one or more substituents selectedfrom the group consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)cyano, 5) —CO(C₁-C₆)-alkyl, 6) —CO₂(C₁-C₆)-alkyl, 7) —CONR⁸R⁹, 8)—NR⁸R⁹; 9) —O(C═O)—(C₁-C₆)-alkyl, and 10) —O(C═O)NR⁸R⁹; R¹¹ is: (a)halo, (b) —OH, (c) —O[(C═O)O_(r)]_(s)(C₁-C₆)-alkyl, (d)—O[(C═O)O_(r)]_(s)aryl, (e) —O[(C═O)O_(r)]_(s)heteroaryl, (f) cyano, (g)—NR⁸R⁹, (h) —O(CO)NR⁸R⁹, (i) —CO(C₁-C₆)-alkyl, (j) —CO₂(C₁-C₆)-alkyl,(k) —CONR⁸R⁹, (l) aryl, which may optionally be substituted with one ormore substituents selected from the group consisting of: 1) halo, 2)—OH, 3) (C₁-C₆)-alkyl, 4) (C₁-C₄)-perfluoroalkyl, 5) (C₁-C₆)-alkyloxy,6) cyano, 7) —CO(C₁-C₆)-alkyl, 8) —CO₂(C₁-C₆)-alkyl, 9) —CONR⁸R⁹, 10)—NR⁸R⁹, 11) —O(C═O)—(C₁-C₆)-alkyl, and 12) —O(C═O)NR⁸R⁹, (m) heteroaryloptionally substituted with one or more substituents selected from thegroup consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, 4)aryl-(C₁-C₆)alkyloxy-, 5) (C₁-C₄)-perfluoroalkyl, 6) (C₁-C₆)-alkyloxy,7) cyano, 8) —CO(C₁-C₆)-alkyl, 9) —CO₂(C₁-C₆)-alkyl, 10) —CONR⁸R⁹, 11)—NR⁸R⁹, 12) —O(C═O)—(C₁-C₆)-alkyl, and 13) —O(C═O)NR⁸R⁹, (o) heterocycloother than heteroaryl which is optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, 4) (C₁-C₄)-perfluoroalkyl, 5) (C₁-C₆)-alkyloxy, 6) cyano,7) —CO(C₁-C₆)-alkyl, 8) —CO₂(C₁-C₆)-alkyl, 9) —CONR⁸R⁹, 10) —NR⁸R⁹, 11)—O(C═O)—(C₁-C₆)-alkyl, and 12) —O(C═O)NR⁸R⁹, (p) —(C₁-C₁₀)-alkyl, whichmay optionally be substituted with one or more substituents selectedfrom the group consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)cyano, 5) —COOH, 6) —CO(C₁-C₆)-alkyl, 7) —CO₂(C₁-C₆)-alkyl, 8) —CONR⁸R⁹,9) —NR⁸R⁹, 10) —O(C═O)—(C₁-C₆)-alkyl, and 11) —O(C═O)NR⁸R⁹, (q)—O(CH₂)_(m)-heteroaryl as defined above; R¹² is: (a) halo, (b) —OH, (c)—O[(C═O)O_(r)]_(s)(C₁-C₆)-alkyl, (d) —O[(C═O)O_(r)]_(s)aryl, (e)—O[(C═O)O_(r)]_(s)heteroaryl, (f) cyano, (g) nitro, (h) —NR⁸R⁹, (i)—O(CO)NR⁸R⁹, (j) —CO(C₁-C₆)-alkyl, (k) —CO₂(C₁-C₆)-alkyl, (l) —CONR⁸R⁹,(m) aryl, which may optionally be substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, 4) (C₁-C₄)-perfluoroalkyl, 5) (C₂-C₆)-alkenyl, 6)(C₂-C₆)-alkynyl, 7) (C₁-C₆)-alkyloxy, 8) cyano, 9) —COOH, 10)—CO(C₁-C₆)-alkyl, 11) —CO₂(C₁-C₆)-alkyl, 12) —CONR⁸R⁹, 13) —NR⁸R⁹, 14)—O(C═O)—(C₁-C₆)-alkyl, and 15) —O(C═O)NR⁸R⁹, (n) heteroaryl optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, 4)(C₁-C₄)-perfluoroalkyl, 5) (C₁-C₆)-alkyloxy, 6) cyano, 7) —COOH, 8)—CO(C₁-C₆)-alkyl, 9) —CO₂(C₁-C₆)-alkyl, 10) —CONR⁸R⁹, 11) —NR⁸R⁹, 12)—O(C═O)—(C₁-C₆)-alkyl, and 13) —O(C═O)NR⁸R⁹, (o) heterocyclo other thanheteroaryl which is optionally substituted with one or more substituentsselected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, 4) (C₁-C₄)-perfluoroalkyl, 5) (C₁-C₆)-alkyloxy, 6) cyano,7) —CO(C₁-C₆)-alkyl, 8) —CO₂(C₁-C₆)-alkyl, 9) —CONR⁸R⁹, 10) —NR⁸R⁹, 11)—O(C═O)—(C₁-C₆)-alkyl, and 12) —O(C═O)NR⁸R⁹, (p) —(C₁-C₁₀)-alkyl, whichmay optionally be substituted with one or more substituents selectedfrom the group consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)cyano, 5) —CO(C₁-C₆)-alkyl, 6) —CO₂(C₁-C₆)-alkyl, 7) —CONR⁸R⁹, 8)—NR⁸R⁹, 9) —O(C═O)—(C₁-C₆)-alkyl, and 10) —O(C═O)NR⁸R⁹, (q) ═O; R¹⁴ is:(a) halo, (b) —OH, (c) —O[(C═O)O_(r)]_(s)(C₁-C₆)-alkyl, (d)—O[(C═O)O_(r)]_(s)aryl, (e) —O[(C═O)O_(r)]_(s)heteroaryl, (f) cyano, (g)nitro, (h) —NR⁸R⁹, (i) —O(CO)NR⁸R⁹, (j) —CO(C₁-C₆)-alkyl, (k)—CO₂(C₁-C₆)-alkyl, (l) —CONR⁸R⁹, (m) aryl, which may optionally besubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, 4)(C₁-C₄)-perfluoroalkyl, 5) (C₁-C₆)-alkyloxy, 6) cyano, 7)—CO(C₁-C₆)-alkyl, 8) —CO₂(C₁-C₆)-alkyl, 9) —CONR⁸R⁹, 10) —NR⁸R⁹, 11)—O(C═O)—(C₁-C₆)-alkyl, and 12) —O(C═O)NR⁸R⁹, (n) heteroaryl optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, 4)(C₁-C₄)-perfluoroalkyl, 5) (C₁-C₆)-alkyloxy, 6) cyano, 7)—CO(C₁-C₆)-alkyl, 8) —CO₂(C₁-C₆)-alkyl, 9) —CONR⁸R⁹, 10) —NR⁸R⁹, 11)—O(C═O)—(C₁-C₆)-alkyl, and 12) —O(C═O)NR⁸R⁹, (o) heterocyclo other thanheteroaryl which is optionally substituted with one or more substituentsselected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, 4) (C₁-C₄)-perfluoroalkyl, 5) (C₁-C₆)-alkyloxy, 6) cyano,7) —CO(C₁-C₆)-alkyl, 8) —CO₂(C₁-C₆)-alkyl, 9) —CONR⁸R⁹, 10) —NR⁸R⁹, 11)—O(C═O)—(C₁-C₆)-alkyl, and 12) —O(C═O)NR⁸R⁹, (p) —(C₁-C₁₀)-alkyl, whichmay optionally be substituted with one or more substituents selectedfrom the group consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)cyano, 5) —CO(C₁-C₆)-alkyl, 6) —CO₂(C₁-C₆)-alkyl, 7) —CONR⁸R⁹, 8)—NR⁸R⁹, 9) —O(C═O)—(C₁-C₆)-alkyl, and 10) —O(C═O)NR⁸R⁹; R¹⁹ is: (a)hydrogen, (b) (C₁-C₆)-alkyl, (c) —CO(C₁-C₆)-alkyl, (d) —CO(C₁-C₆)-aryl,(e) —CO(C₁-C₆)-heteroaryl, (f) —CO₂(C₁-C₆)-alkyl, (g) CO₂(C₁-C₆)-aryl,(h) CO₂(C₁-C₆)-heteroaryl, or (i) —CONR⁸R⁹; R²⁰ is: (a) hydrogen, (b)halo, (c) —OH, (d) —O[(C═O)O_(r)]_(s)(C₁-C₆)-alkyl, (e)—O[(C═O)O_(r)]_(s)aryl, (f) —O[(C═O)O_(r)]_(s)heteroaryl, (g) cyano, (h)nitro, (i) —NR⁸R⁹, (j) —O(CO)NR⁸R⁹, (k) —CO(C₁-C₆)-alkyl, (l)—CO₂(C₁-C₆)-alkyl, (m) —CONR⁸R⁹, (n) aryl, which may optionally besubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, 4)(C₁-C₄)-perfluoroalkyl, 5) (C₁-C₆)-alkyloxy, 6) cyano, 7)—CO(C₁-C₆)-alkyl, 8) —CO₂(C₁-C₆)-alkyl, 9) —CONR⁸R⁹, 10) —NR⁸R⁹, 11)—O(C═O)—(C₁-C₆)-alkyl, and 12) —O(C═O)NR⁸R⁹, (o) heteroaryl optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, 4)(C₁-C₄)-perfluoroalkyl, 5) (C₁-C₆)-alkyloxy, 6) cyano, 7)—CO(C₁-C₆)-alkyl, 8) —CO₂(C₁-C₆)-alkyl, 9) —CONR⁸R⁹, 10) —NR⁸R⁹, 11)—O(C═O)—(C₁-C₆)-alkyl, and 12) —O(C═O)NR⁸R⁹, (p) heterocyclo other thanheteroaryl which is optionally substituted with one or more substituentsselected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, 4) (C₁-C₄)-perfluoroalkyl, 5) (C₁-C₆)-alkyloxy, 6) cyano,7) —CO(C₁-C₆)-alkyl, 8) —CO₂(C₁-C₆)-alkyl, 9) —CONR⁸R⁹, and 10) —NR⁸R⁹,(q) —(C₁-C₁₀)-alkyl, which may optionally be substituted with one ormore substituents selected from the group consisting of: 1) halo, 2)—OH, 3) (C₁-C₆)-alkyloxy, 4) cyano, 5) —CO(C₁-C₆)-alkyl, 6)—CO₂(C₁-C₆)-alkyl, 7) —CONR⁸R⁹, 8) —NR⁸R⁹, 9) —O(C═O)—(C₁-C₆)-alkyl, and10) —O(C═O)NR⁸R⁹; R²¹ is: (a) C₁-C₁₀-alkyl optionally substituted withone or more R¹¹'s, (b) aryl optionally substituted with one or more R's,or (c) heterocyclyl optionally substituted with one or more R¹¹'s; m is1 to 4; p is 1 or 2; r is 0 to 4; and s is 0 to
 3. 13. The compound ofclaim 1, wherein: R¹ is an aryl or heterocyclic ring, which may beoptionally substituted with one or more R¹⁰'s; R² and R³ areindependently: (a) halo, (b) (C₁-C₆)-alkoxy optionally substituted withone or more R¹¹'s, (c) (C₁-C₄)-perfluoroalkyl, (d) hydrogen, (e)C₁-C₁₀-alkyl optionally substituted with one or more R¹¹'s, (f) aryloptionally substituted with one or more R¹¹'s, or (g) heterocyclyloptionally substituted with one or more R¹¹'s, provided that both R² andR³ are not simultaneously hydrogen; R⁴ is: (a) hydrogen, (b)C₁-C₁₀-alkyl, (c) —CO(C₁-C₆)-alkyl, (d) —CO(C₁-C₆)-aryl, or (e)—CO(C₁-C₆)-heteroaryl; R⁵ is

Q is a O, C═O, N, NR¹⁹ or CR¹⁰; T is O, S, C═O, N or NR¹⁹; X, U, V and Ware independently O, C═O or CR²⁰; R⁸ and R⁹ are independently: (a)hydrogen, (b) —[(C═O)O_(r)]_(s)aryl, wherein the aryl may be optionallysubstituted with one or more R¹⁴'s, (c) —[(C═O)O_(r)]_(s)(C₁-C₈)alkyl,wherein the alkyl may be optionally substituted with one or more R¹⁴'s,(d) heterocyclyl optionally substituted with one or more R¹⁴'s; R¹⁰ is:(a) halo, (b) —O[(C═O)O_(r)]_(s)(C₁-C₆)-alkyl, (c)—O[(C═O)O_(r)]_(s)aryl, (d) —O[(C═O)O_(r)]_(s)heteroaryl, (e) cyano, (f)nitro, (g) aryl, which may optionally be substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, 4) (C₁-C₄)-perfluoroalkyl, 5) (C₁-C₆)-alkyloxy, and 6)cyano, (h) heteroaryl optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, 4) (C₁-C₄)-perfluoroalkyl, 5) (C₁-C₆)-alkyloxy, and 6)cyano, (i) heterocyclo other than heteroaryl which is optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, 4)(C₁-C₄)-perfluoroalkyl, 5) (C₁-C₆)-alkyloxy, and 6) cyano, (j)—(C₁-C₁₀)-alkyl, which may optionally be substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyloxy, and 4) cyano; R¹¹ is: (a) halo, (b) —OH, (c)—O[(C═O)O_(r)]_(s)(C₁-C₆)-alkyl, (d) —O[(C═O)O_(r)]_(s)aryl, (e)—O[(C═O)O_(r)]_(s)heteroaryl, (f) —NR⁸R⁹, provided that neither R⁸ norR⁹ in this instance is —C(═O)— phenyl, (g) —O(CO)NR⁸R⁹, (h) aryl, whichmay optionally be substituted with one or more substituents selectedfrom the group consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, 4)(C₁-C₄)-perfluoroalkyl, 5) (C₁-C₆)-alkyloxy, and 6) cyano, (i)heteroaryl optionally substituted with one or more substituents selectedfrom the group consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, 4)aryl-(C₁-C₆)alkyloxy-, 5) (C₁-C₄)-perfluoroalkyl, 6) (C₁-C₆)-alkyloxy,and 7) cyano, (j) heterocyclo other than heteroaryl which is optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, 4)(C₁-C₄)-perfluoroalkyl, 5) (C₁-C₆)-alkyloxy, and 6) cyano, (k)—(C₁-C₁₀)-alkyl, which may optionally be substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyloxy, 4) cyano, and 5) —COOH, (l) —O(CH₂)_(m)-heteroaryl asdefined above; R¹² is: (a) halo, (b) —O[(C═O)O_(r)]_(s)(C₁-C₆)-alkyl,(c) —O[(C═O)O_(r)]_(s)aryl, (d) —O[(C═O)O_(r)]_(s)heteroaryl, (e) aryl,which may optionally be substituted with one or more substituentsselected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, 4) (C₁-C₄)-perfluoroalkyl, 5) (C₁-C₆)-alkyloxy, and 6)cyano, (f) heteroaryl optionally substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, 4) (C₁-C₄)-perfluoroalkyl, 5) (C₁-C₆)-alkyloxy, 6) cyano,and 7) —COOH, (g) heterocyclo other than heteroaryl which is optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, 4)(C₁-C₄)-perfluoroalkyl, 5) (C₁-C₆)-alkyloxy, and 6) cyano, (h)—(C₁-C₁₀)-alkyl, which may optionally be substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyloxy, and 4) cyano, (i) ═O; R¹⁴ is: (a) halo, (b) —OH, (c)—O[(C═O)O_(r)]_(s)(C₁-C₆)-alkyl, (d) —O[(C═O)O_(r)]_(s)aryl, (e)—O[(C═O)O_(r)]_(s)heteroaryl, (f) aryl, which may optionally besubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, 4)(C₁-C₄)-perfluoroalkyl, 5) (C₁-C₆)-alkyloxy, and 6) cyano, (g)heteroaryl optionally substituted with one or more substituents selectedfrom the group consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, 4)(C₁-C₄)-perfluoroalkyl, 5) (C₁-C₆)-alkyloxy, and 6) cyano, (h)heterocyclo other than heteroaryl which is optionally substituted withone or more substituents selected from the group consisting of: 1) halo,2) —OH, 3) (C₁-C₆)-alkyl, 4) (C₁-C₄)-perfluoroalkyl, 5)(C₁-C₆)-alkyloxy, and 6) cyano, (i) —(C₁-C₁₀)-alkyl, which mayoptionally be substituted with one or more substituents selected fromthe group consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, and 4)cyano; R¹⁹ is: (a) hydrogen, (b) (C₁-C₆)-alkyl, (c) —CO(C₁-C₆)-alkyl,(d) —CO₂(C₁-C₆)-alkyl, or (e) —CONR⁸R⁹; R²⁰ is: (a) hydrogen, (b) halo,(c) —OH, (d) —O[(C═O)O_(r)]_(s)(C₁-C₆)-alkyl, (e) aryl, which may beoptionally substituted with one or more substituents selected from thegroup consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, 4)(C₁-C₄)-perfluoroalkyl, 5) (C₁-C₆)-alkyloxy, and 6) cyano, (f)heteroaryl optionally substituted with one or more substituents selectedfrom the group consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, 4)(C₁-C₄)-perfluoroalkyl, 5) (C₁-C₆)-alkyloxy, and 6) cyano, (g)heterocyclo other than heteroaryl which is optionally substituted withone or more substituents selected from the group consisting of: 1) halo,2) —OH, 3) (C₁-C₆)-alkyl, 4) (C₁-C₄)-perfluoroalkyl, 5)(C₁-C₆)-alkyloxy, and 6) cyano, (h) —(C₁-C₁₀)-alkyl, which mayoptionally be substituted with one or more substituents selected fromthe group consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, and 4)cyano; m is 1 to 3; r is 0 to 3; and s is 0 to
 2. 14. The compound ofclaim 1, wherein: R¹ is an aryl or heterocyclic ring, which may beoptionally substituted with one or more R¹⁰'s; R² and R³ areindependently: (a) hydrogen, (b) C₁-C₁₀-alkyl optionally substitutedwith one or more R¹¹'s, (c) aryl optionally substituted with one or moreR¹¹'s, or (d) heterocyclyl optionally substituted with one or moreR¹¹'s, provided that both R² and R³ are not simultaneously hydrogen; R⁴is hydrogen or C₁-C₁₀-alkyl; R⁵ is

Q is a O, C═O, NR¹⁹ or CR²⁰; T is O, S, C═O or NR¹⁹; X, U, V and W areindependently C═O or CR²⁰; R⁸ and R⁹ are independently: (a) hydrogen,(b) —[(C═O)O_(r)]_(s)aryl, (c) —[(C═O)O_(r)]_(s)(C₁-C₈)alkyl, or (d)heterocyclyl; R¹⁰ is: (a) halo, (b) —O[(C═O)O_(r)]_(s)(C₁-C₆)-alkyl, (c)—O[(C═O)O_(r)]_(s)heteroaryl, (d) aryl, (e) heteroaryl, (f) heterocyclo,or (g) —(C₁-C₁₀)-alkyl; R¹¹ is: (a) —OH, (b)—O[(C═O)O_(r)]_(s)(C₁-C₆)-alkyl, (c) —O[(C═O)O_(r)]_(s)aryl, (d)—O[(C═O)O_(r)]_(s)heteroaryl, (e) —O(CO)NR⁸R⁹, (f) aryl, (g) heteroaryl,(h) heterocyclo, (i) —(C₁-C₁₀)-alkyl, or (j) —O(CH₂)_(m)-heteroaryl asdefined above; R¹² is: (a) halo, (b) —O[(C═O)O_(r)]_(s)(C₁-C₆)-alkyl,(c) —O[(C═O)O_(r)]_(s)aryl, (d) —O[(C═O)O_(r)]_(s)heteroaryl, (e) aryl,(f) heteroaryl, (g) heterocyclo, (h) —(C₁-C₁₀)-alkyl, and (i) ═O; R¹⁹is: (a) hydrogen, (b) (C₁-C₆)-alkyl, or (c) —CONR⁸R⁹; R²⁰ is: (a)hydrogen, (b) halo, (c) —O[(C═O)O_(r)]_(s)(C₁-C₆)-alkyl, (d) aryl, (e)heteroaryl, (f) heterocyclo, (g) —(C₁-C₁₀)-alkyl; m is 1 to 3; r is 0 to3; and s is 0 to
 2. 15. The compound of claim 1, wherein: R¹ is phenylor pyridinyl, which may be optionally substituted with one or moreR¹⁰'s; R² and R³ are independently: (a) hydrogen, (b) C₁-C₁₀-alkyloptionally substituted with one or more R¹¹'s; (c) aryl optionallysubstituted with one or more R¹¹'s, or (d) heterocyclyl optionallysubstituted with one or more R¹¹'s, provided that both R² and R³ are notsimultaneously hydrogen; R⁴ is hydrogen; R⁵ is

Q is a O, C═O or CR²⁰; T is O, S or NR¹⁹; X, U, V and W are CR²⁰; R⁸ andR⁹ are independently: (a) hydrogen, (b) aryl, (c) —(C₁-C₈)alkyl, or (d)heterocyclyl; R¹⁰ is: (a) halo, (b) —O(C₁-C₆)-alkyl, (c) —Oheteroaryl,(d) aryl, (e) heteroaryl-, (f) —(C₁-C₁₀)-alkyl; R¹¹ is: (a)—O(C₁-C₆)-alkyl, (b) —Oaryl, (c) —Oheteroaryl, (d) —O(CO)NR⁸R⁹, (e)aryl, (f) heteroaryl, (g) —(C₁-C₁₀)-alkyl; R¹² is: (a) halo, (b)—O(C₁-C₆)-alkyl, (c) —Oaryl, (d) —Oheteroaryl, (e) aryl, (f) heteroaryl,(g) —(C₁-C₁₀)-alkyl, and (h) ═O; R¹⁹ is: (a) hydrogen, (b)(C₁-C₆)-alkyl, or (c) —CONR⁸R⁹; and R²⁰ is: (a) hydrogen, (b) halo, (c)—O(C₁-C₆)-alkyl, (d) aryl, (e) heteroaryl, (f) heterocyclo, or (g)—(C₁-C₁₀)-alkyl.
 16. The compound of claim 1 wherein the compound isselected from the group of compounds set forth in the examples.
 17. Apharmaceutical composition comprising a therapeutically effective amountof at least one compound of claim 1 and a pharmaceutically acceptablevehicle or carrier thereof.
 18. A method of treating or preventingarrhythmia comprising administering to a patient in need thereof aneffective amount of at least one compound of formula I

or a stereoisomer or a tautomer or a pharmaceutically acceptable salt ora prodrug thereof, wherein: R¹ is an aryl or heterocyclic ring, whichmay be optionally substituted with one or more R¹⁰'s; R² and R³ areindependently: (a) halo, (b) (C₁-C₆)-alkoxy optionally substituted withone or more R¹¹'s, (c) (C₁-C₄)-perfluoroalkyl, (d)(C₁-C₆)-alkyl-S(O)_(n)—, (e) aryl-(CH₂)_(r)—S(O)_(n)—, (f) cyano, (g)—CO₂H, (h) —CO(C₁-C₆)-alkyl, (i) —CO₂(C₁-C₆)-alkyl, (j) —CONR⁸R⁹, (k)—O(CO)NR⁸R⁹, (l) —NR⁸(CO)NR⁸R⁹, (m) —NR⁸R⁹, (n) hydrogen, (o)C₁-C₁₀-alkyl optionally substituted with one or more R¹¹'s, (p)(C₂-C₁₀)-alkenyl optionally substituted with one or more R¹¹'s, (q)(C₂-C₁₀)-alkynyl optionally substituted with one or more R¹¹'s, (r) aryloptionally substituted with one or more R¹¹'s, (s) heterocyclyloptionally substituted with one or more R¹¹'s, or (t) —NR⁸(CO)OR²¹,provided that both R² and R³ are not simultaneously hydrogen; R⁴ is: (a)hydrogen, (b) C₁-C₁₀-alkyl, (c) —CO(C₁-C₆)-alkyl, (d) —COaryl, (e)—COheterocyclyl, (f) —CO₂(C₁-C₆)-alkyl, (g) —CO₂aryl, (h)—CO₂heterocyclyl, (i) —CONR⁸R⁹, (j) —S(O)_(n)-alkyl, (k) —S(O)_(n)-aryl,(l) —S(O)_(n)-heterocyclyl, or (m) —S(O)_(n)—NR⁸R⁹; R⁵ is

wherein the dashed line(s) represent an optional double bond; T is O, S,C═O, N, NR¹⁹ or C(R²⁰)_(p); Q, X, U, V and W are independently O, S,C═O, N, NR¹⁹ or C(R²⁰)_(p), provided that Q is not C(R²⁰)_(p) when X isN or NR¹⁹; R⁸ and R⁹ are independently: (a) hydrogen, (b)—[(C═O)O_(r)]_(s)aryl, wherein the aryl may be optionally substitutedwith one or more R¹⁴'s, (c) —[(C═O)O_(r)]_(s)(C₂-C₈)-alkenyl, whereinthe alkenyl may be optionally substituted with one or more R¹⁴'s, (d)—[(C═O)O_(r)]_(s)(C₁-C₈)alkyl, wherein the alkyl may be optionallysubstituted with one or more R¹⁴'s, (e) —S(O)_(p)(C₁-C₈)alkyl, whereinthe alkyl may be optionally substituted with one or more R¹⁴'s, (f)—S(O)_(p)NR¹⁶R¹⁷, (g) —C(═NR¹⁸)(NR¹⁶R¹⁷), or (h) heterocyclyl optionallysubstituted with one or more R¹⁴'s, or R⁸ and R⁹ are taken together withthe nitrogen to which both are attached to form a 3- to 8-membered ring,which may optionally contain 1-4 heteroatoms selected from N, O, and Sand be optionally substituted with one or more R¹⁴'s; R¹⁰ is: (a) halo,(b) —OH, (c) —O[(C═O)O_(r)]_(s)(C₁-C₆)-alkyl, (d)—O[(C═O)O_(r)]_(s)(C₂-C₆)-alkenyl, (e) —O[(C═O)O_(r)]_(s)aryl, (f)—O[(C═O)O_(r)]_(s)heteroaryl, (g) (C₁-C₆)-alkyl-S(O)_(n)—, (h)aryl-(C₁-C₆)alkyloxy-, (i) cyano, (j) nitro, (k) —NR⁸R⁹, (l)—O(CO)NR⁸R⁹, (m) —CHO, (n) —COOH, (o) —CO(C₁-C₆)-alkyl, (p)—CO₂(C₁-C₆)-alkyl, (q) —CONR⁸R⁹, (r) aryl, which may optionally besubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, 4)(C₁-C₄)-perfluoroalkyl, 5) (C₂-C₆)-alkenyl, 6) (C₂-C₆)-alkynyl, 7)(C₁-C₆)-alkyloxy, 8) (C₁-C₆)-alkyl-S(O)_(n)—, 9) cyano, 10) —COOH, 11)—CO(C₁-C₆)-alkyl, 12) —CO₂(C₁-C₆)-alkyl, 13) —CONR⁸R⁹, 14) —NR⁸R⁹, 15)—O(C═O)—(C₁-C₆)-alkyl, and 16) —O(C═O)NR⁸R⁹, (s) heteroaryl optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, 4)(C₁-C₄)-perfluoroalkyl, 5) (C₂-C₆)-alkenyl, 6) (C₂-C₆)-alkynyl, 7)(C₁-C₆)-alkyloxy, 8) (C₁-C₆)-alkyl-S(O)_(n)—, 9) cyano, 10) —COOH, 11)—CO(C₁-C₆)-alkyl, 12) —CO₂(C₁-C₆)-alkyl, 13) —CONR⁸R⁹, 14) —NR⁸R⁹, 15)—O(C═O)—(C₁-C₆)-alkyl, and 16) —O(C═O)NR⁸R⁹, (t) heterocyclo other thanheteroaryl which is optionally substituted with one or more substituentsselected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, 4) (C₁-C₄)-perfluoroalkyl, 5) (C₂-C₆)-alkenyl, 6)(C₂-C₆)-alkynyl, 7) (C₁-C₆)-alkyloxy, 8) (C₁-C₆)-alkyl-S(O)_(n)—, 9)cyano, 10) —COOH, 11) —CO(C₁-C₆)-alkyl, 12) —CO₂(C₁-C₆)-alkyl, 13)—CONR⁸R⁹, 14) —NR⁸R⁹, 15) —O(C═O)—(C₁-C₆)-alkyl, and 16) —O(C═O)NR⁸R⁹,(u) benzyl-S(O)_(n)—, (v) (C₂-C₁₀)-alkenyl, which may optionally besubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) cyano, 6) —COOH, 7) —CO(C₁-C₆)-alkyl, 8)—CO₂(C₁-C₆)-alkyl, 9) —CONR⁸R⁹, 10) —NR⁸R⁹, 11) —O(C═O)—(C₁-C₆)-alkyl,and 12) —O(C═O)NR⁸R⁹, (w) (C₂-C₁₀)-alkynyl wherein alkynyl is optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) cyano, 6) —COOH, 7) —CO(C₁-C₆)-alkyl, 8)—CO₂(C₁-C₆)-alkyl, 9) —CONR⁸R⁹, 10) —NR⁸R⁹, 11) —O(C═O)—(C₁-C₆)-alkyl,and 12) —O(C═O)NR⁸R⁹, (x) —(C₁-C₁₀)-alkyl, which may optionally besubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) benzyl-S(O)_(n)—, 6) cyano, 7) —COOH, 8)—CO(C₁-C₆)-alkyl, 9) —CO₂(C₁-C₆)-alkyl, 10) —CONR⁸R⁹, 11) —NR⁸R⁹, 12)—O(C═O)—(C₁-C₆)-alkyl, and 13) —O(C═O)NR⁸R⁹; R¹¹ is: (a) halo, (b) —OH,(c) —O[(C═O)O_(r)]_(s)(C₁-C₆)-alkyl, (d)—O[(C═O)O_(r)]_(s)(C₂-C₆)-alkenyl, (e) —O[(C═O)O_(r)]_(s)aryl, (f)—O[(C═O)O_(r)]_(s)heteroaryl, (g) (C₁-C₆)-alkyl-S(O)_(n)—, (h)aryl-(C₁-C₆)alkyloxy-, (i) cyano, (j) —NR⁸R⁹, (k) —O(CO)NR⁸R⁹, (l)—COOH, (m) —CO(C₁-C₆)-alkyl, (n) —CO₂(C₁-C₆)-alkyl, (o) —CONR⁸R⁹, (p)aryl, which may optionally be substituted with one or more substituentsselected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, 4) aryl-(C₁-C₆)alkyloxy-, 5) (C₁-C₄)-perfluoroalkyl, 6)(C₂-C₆)-alkenyl, 7) (C₂-C₆)-alkynyl, 8) (C₁-C₆)-alkyloxy, 9)(C₁-C₆)-alkyl-S(O)_(n)—, 10) cyano, 11) —COOH, 12) —CO(C₁-C₆)-alkyl, 13)—CO₂(C₁-C₆)-alkyl, 14) —CONR⁸R⁹, 15) —NR⁸R⁹, 16) —O(C═O)—(C₁-C₆)-alkyl,and 17) —O(C═O)NR⁸R⁹, (q) heteroaryl optionally substituted with one ormore substituents selected from the group consisting of: 1) halo, 2)—OH, 3) (C₁-C₆)-alkyl, 4) aryl-(C₁-C₆)alkyloxy-, 5)(C₁-C₄)-perfluoroalkyl, 6) (C₂-C₆)-alkenyl, 7) (C₂-C₆)-alkynyl, 8)(C₁-C₆)-alkyloxy, 9) (C₁-C₆)-alkyl-S(O)_(n)—, 10) cyano, 11) —COOH, 12)—CO(C₁-C₆)-alkyl, 13) —CO₂(C₁-C₆)-alkyl, 14) —CONR⁸R⁹, 15) —NR⁸R⁹, 16)—O(C═O)—(C₁-C₆)-alkyl, and 17) —O(C═O)NR⁸R⁹, (r) heterocyclo other thanheteroaryl which is optionally substituted with one or more substituentsselected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, 4) aryl-(C₁-C₆)alkyloxy-, 5) (C₁-C₄)-perfluoroalkyl, 6)(C₂-C₆)-alkenyl, 7) (C₂-C₆)-alkynyl, 8) (C₁-C₆)-alkyloxy, 9)(C₁-C₆)-alkyl-S(O)_(n)—, 10) cyano, 11) —COOH, 12) —CO(C₁-C₆)-alkyl, 13)—CO₂(C₁-C₆)-alkyl, 14) —CONR⁸R⁹, 15) —NR⁸R⁹, 16) —O(C═O)—(C₁-C₆)-alkyl,and 17) —O(C═O)NR⁸R⁹, (s) —(C₂-C₁₀)-alkenyl, which may optionally besubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) phenyl-(C₁-C₆)-alkyloxy-, 6) cyano, 7) —CHO,8) —COOH, 9) —CO(C₁-C₆)-alkyl, 10) —CO₂(C₁-C₆)-alkyl, 11) —CONR⁸R⁹, 12)—NR⁸R⁹, 13) aryl, 14) heteroaryl as defined above, 15) heterocyclo otherthan heteroaryl as defined above, 16) —O(C═O)—(C₁-C₆)-alkyl, and 17)—O(C═O)NR⁸R⁹, (t) (C₂-C₁₀)-alkynyl wherein alkynyl is optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) phenyl-(C₁-C₆)-alkyloxy-, 6) cyano, 7)vinyl, 8) —CHO, 9) —COOH, 10) —CO(C₁-C₆)-alkyl, 11) —CO₂(C₁-C₆)-alkyl,12) —CONR⁸R⁹, 13) —NR⁸R⁹, 14) aryl, wherein aryl is defined as above,15) heteroaryl as defined above, 16) heterocyclyl other than heteroarylas defined above, 17) —O(C═O)—(C₁-C₆)-alkyl, and 18) —O(C═O)NR⁸R⁹, (u)—(C₁-C₁₀)-alkyl, which may optionally be substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyloxy, 4) (C₁-C₆)-alkyl-S(O)_(n)—, 5) benzyl-S(O)_(n)—, 6)cyano, 7) —COOH, 8) —CO(C₁-C₆)-alkyl, 9) —CO₂(C₁-C₆)-alkyl, 10)—CONR⁸R⁹, 11) —NR⁸R⁹, 12) —O(C═O)—(C₁-C₆)-alkyl, and 13) —O(C═O)NR⁸R⁹,(v) —O(CH₂)_(m)-heteroaryl as defined above; R¹² is: (a) halo, (b) —OH,(c) —O[(C═O)O_(r)]_(s)(C₁-C₆)-alkyl, (d)—O[(C═O)O_(r)]_(s)(C₂-C₆)-alkenyl, (e) —O[(C═O)O_(r)]_(s)aryl, (f)—O[(C═O)O_(r)]_(s)heteroaryl, (g) (C₁-C₆)-alkyl-S(O)_(n)—, (h)aryl-(C₁-C₆)alkyloxy-, (i) cyano, (j) nitro, (k) —NR⁸R⁹, (l)—O(CO)NR⁸R⁹, (m) —CHO, (n) —COOH, (o) —CO(C₁-C₆)-alkyl, (p)—CO₂(C₁-C₆)-alkyl, (q) —CONR⁸R⁹, (r) aryl, which may optionally besubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, 4)(C₁-C₄)-perfluoroalkyl, 5) (C₂-C₆)-alkenyl, 6) (C₂-C₆)-alkynyl, 7)(C₁-C₆)-alkyloxy, 8) (C₁-C₆)-alkyl-S(O)_(n)—, 9) cyano, 10) —COOH, 11)—CO(C₁-C₆)-alkyl, 12) —CO₂(C₁-C₆)-alkyl, 13) —CONR⁸R⁹, 14) —NR⁸R⁹, 15)—O(C═O)—(C₁-C₆)-alkyl, and 16) —O(C═O)NR⁸R⁹, (s) heteroaryl optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, 4)(C₁-C₄)-perfluoroalkyl, 5) (C₂-C₆)-alkenyl, 6) (C₂-C₆)-alkynyl, 7)(C₁-C₆)-alkyloxy, 8) (C₁-C₆)-alkyl-S(O)_(n)—, 9) cyano, 10) —COOH, 11)—CO(C₁-C₆)-alkyl, 12) —CO₂(C₁-C₆)-alkyl, 13) —CONR⁸R⁹, 14) —NR⁸R⁹, 15)—O(C═O)—(C₁-C₆)-alkyl, and 16) —O(C═O)NR⁸R⁹, (t) heterocyclo other thanheteroaryl which is optionally substituted with one or more substituentsselected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, 4) (C₁-C₄)-perfluoroalkyl, 5) (C₂-C₆)-alkenyl, 6)(C₂-C₆)-alkynyl, 7) (C₁-C₆)-alkyloxy, 8) (C₁-C₆)-alkyl-S(O)_(n)—, 9)cyano, 10) —COOH, 11) —CO(C₁-C₆)-alkyl, 12) —CO₂(C₁-C₆)-alkyl, 13)—CONR⁸R⁹, 14) —NR⁸R⁹, 15) —O(C═O)—(C₁-C₆)-alkyl, and 16) —O(C═O)NR⁸R⁹,(u) benzyl-S(O)_(n)—, (v) (C₂-C₁₀)-alkenyl, which may optionally besubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) cyano, 6) —COOH, 7) —CO(C₁-C₆)-alkyl, 8)—CO₂(C₁-C₆)-alkyl, 9) —CONR⁸R⁹, 10) —NR⁸R⁹, 11) —O(C═O)—(C₁-C₆)-alkyl,and 12) —O(C═O)NR⁸R⁹, (w) (C₂-C₁₀)-alkynyl wherein alkynyl is optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) cyano, 6) —COOH, 7) —CO(C₁-C₆)-alkyl, 8)—CO₂(C₁-C₆)-alkyl, 9) —CONR⁸R⁹, 10) —NR⁸R⁹, 11) —O(C═O)—(C₁-C₆)-alkyl,and 12) —O(C═O)NR⁸R⁹, (x) —(C₁-C₁₀)-alkyl, which may optionally besubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) benzyl-S(O)_(n)—, 6) cyano, 7) —COOH, 8)—CO(C₁-C₆)-alkyl, 9) —CO₂(C₁-C₆)-alkyl, 10) —CONR⁸R⁹, 11) —NR⁸R⁹, 12)—O(C═O)—(C₁-C₆)-alkyl, and 13) —O(C═O)NR⁸R⁹, (y) ═O; R¹⁴ is: (a) halo,(b) —OH, (c) —O[(C═O)O_(r)]_(s)(C₁-C₆)-alkyl, (d)—O[(C═O)O_(r)]_(s)(C₂-C₆)-alkenyl, (e) —O[(C═O)O_(r)]_(s)aryl, (f)—O[(C═O)O_(r)]_(s)heteroaryl, (g) (C₁-C₆)-alkyl-S(O)_(n)—, (h)aryl-(C₁-C₆)alkyloxy-, (i) cyano, (j) nitro, (k) —NR⁸R⁹, (l)—O(CO)NR⁸R⁹, (m) —CHO, (n) —COOH, (o) —CO(C₁-C₆)-alkyl, (p)—CO₂(C₁-C₆)-alkyl, (q) —CONR⁸R⁹, (r) aryl, which may optionally besubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl-, 4)(C₁-C₄)-perfluoroalkyl, 5) (C₂-C₆)-alkenyl, 6) (C₂-C₆)-alkynyl, 7)(C₁-C₆)-alkyloxy, 8) (C₁-C₆)-alkyl-S(O)_(n)—, 9) cyano, 10) —COOH, 11)—CO(C₁-C₆)-alkyl, 12) —CO₂(C₁-C₆)-alkyl, 13) —CONR⁸R⁹, 14) —NR⁸R⁹, 15)—O(C═O)—(C₁-C₆)-alkyl, and 16) —O(C═O)NR⁸R⁹, (s) heteroaryl optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, 4)(C₁-C₄)-perfluoroalkyl, 5) (C₂-C₆)-alkenyl, 6) (C₂-C₆)-alkynyl, 7)(C₁-C₆)-alkyloxy, 8) (C₁-C₆)-alkyl-S(O)_(n)—, 9) cyano, 10) —COOH, 11)—CO(C₁-C₆)-alkyl, 12) —CO₂(C₁-C₆)-alkyl, 13) —CONR⁸R⁹, 14) —NR⁸R⁹, 15)—O(C═O)—(C₁-C₆)-alkyl, and 16) —O(C═O)NR⁸R⁹, (t) heterocyclo other thanheteroaryl which is optionally substituted with one or more substituentsselected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, 4) (C₁-C₄)-perfluoroalkyl, 5) (C₂-C₆)-alkenyl, 6)(C₂-C₆)-alkynyl, 7) (C₁-C₆)-alkyloxy, 8) (C₁-C₆)-alkyl-S(O)_(n)—, 9)cyano, 10) —COOH, 11) —CO(C₁-C₆)-alkyl, 12) —CO₂(C₁-C₆)-alkyl, 13)—CONR⁸R⁹, 14) —NR⁸R⁹, 15) —O(C═O)—(C₁-C₆)-alkyl, and 16) —O(C═O)NR⁸R⁹,(u) benzyl-S(O)_(n)—, (v) (C₂-C₁₀)-alkenyl, which may optionally besubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) cyano, 6) —COOH, 7) —CO(C₁-C₆)-alkyl, 8)—CO₂(C₁-C₆)-alkyl, 9) —CONR⁸R⁹, 10) —NR⁸R⁹, 11) —O(C═O)—(C₁-C₆)-alkyl,and 12) —O(C═O)NR⁸R⁹, (w) (C₂-C₁₀)-alkynyl wherein alkynyl is optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) cyano, 6) —COOH, 7) —CO(C₁-C₆)-alkyl, 8)—CO₂(C₁-C₆)-alkyl, 9) —CONR⁸R⁹, 10) —NR⁸R⁹, 11) —O(C═O)—(C₁-C₆)-alkyl,and 12) —O(C═O)NR⁸R⁹, (x) —(C₁-C₁₀)-alkyl, which may optionally besubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) benzyl-S(O)_(n)—, 6) cyano, 7) —COOH, 8)—CO(C₁-C₆)-alkyl, 9) —CO₂(C₁-C₆)-alkyl, 10) —CONR⁸R⁹, 11) —NR⁸R⁹, 12)—O(C═O)—(C₁-C₆)-alkyl, and 13) —O(C═O)NR⁸R⁹; R¹⁶ and R¹⁷ areindependently: (a) aryl, which may optionally be substituted with one ormore substituents selected from the group consisting of: 1) halo, 2)—OH, 3) (C₁-C₆)-alkyl, 4) (C₁-C₄)-perfluoroalkyl, 5) (C₂-C₆)-alkenyl, 6)(C₂-C₆)-alkynyl, 7) (C₁-C₆)-alkyloxy, 8) (C₁-C₆)-alkyl-S(O)_(n)—, 9)cyano, 10) —COOH, 11) —CO(C₁-C₆)-alkyl, 12) —CO₂(C₁-C₆)-alkyl, 13)—CONR⁸R⁹, 14) —NR⁸R⁹, 15) —O(C═O)—(C₁-C₆)-alkyl, and 16) —O(C═O)NR⁸R⁹,(b) heteroaryl optionally substituted with one or more substituentsselected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, 4) (C₁-C₄)-perfluoroalkyl, 5) (C₂-C₆)-alkenyl, 6)(C₂-C₆)-alkynyl, 7) (C₁-C₆)-alkyloxy, 8) (C₁-C₆)-alkyl-S(O)_(n)—, 9)cyano, 10) —COOH, 11) —CO(C₁-C₆)-alkyl, 12) —CO₂(C₁-C₆)-alkyl, 13)—CONR⁸R⁹, 14) —NR⁸R⁹, 15) —O(C═O)—(C₁-C₆)-alkyl, and 16) —O(C═O)NR⁸R⁹,(c) heterocyclo other than heteroaryl which is optionally substitutedwith one or more substituents selected from the group consisting of: 1)halo, 2) —OH, 3) (C₁-C₆)-alkyl, 4) (C₁-C₄)-perfluoroalkyl, 5)(C₂-C₆)-alkenyl, 6) (C₂-C₆)-alkynyl, 7) (C₁-C₆)-alkyloxy, 8)(C₁-C₆)-alkyl-S(O)_(n)—, 9) cyano, 10) —COOH, 11) —CO(C₁-C₆)-alkyl, 12)—CO₂(C₁-C₆)-alkyl, 13) —CONR⁸R⁹, 14) —NR⁸R⁹, 15) —O(C═O)—(C₁-C₆)-alkyl,and 16) —O(C═O)NR⁸R⁹, (d) (C₂-C₁₀)-alkenyl, which may optionally besubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) cyano, 6) —COOH, 7) —CO(C₁-C₆)-alkyl, 8)—CO₂(C₁-C₆)-alkyl, 9) —CONR⁸R⁹, 10) —NR⁸R⁹, 11) —O(C═O)—(C₁-C₆)-alkyl,and 12) —O(C═O)NR⁸R⁹, (e) (C₂-C₁₀)-alkynyl wherein alkynyl is optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) cyano, 6) —COOH, 7) —CO(C₁-C₆)-alkyl, 8)—CO₂(C₁-C₆)-alkyl, 9) —CONR⁸R⁹, 10) —NR⁸R⁹, 11) —O(C═O)—(C₁-C₆)-alkyl,and 12) —O(C═O)NR⁸R⁹, (f) —(C₁-C₁₀)-alkyl, which may optionally besubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) benzyl-S(O)_(n)—, 6) cyano, 7) —COOH, 8)—CO(C₁-C₆)-alkyl, 9) —CO₂(C₁-C₆)-alkyl, 10) —CONR⁸R⁹, 11) —NR⁸R⁹, 12)—O(C═O)—(C₁-C₆)-alkyl, and 13) —O(C═O)NR⁸R⁹, or R¹⁶ and R¹⁷ are takentogether with the nitrogen to which both are attached to form a 3- to8-membered ring, which may optionally contain 1-4 heteroatoms selectedfrom N, O, and S and be optionally substituted with one or more R¹⁴'s;R¹⁸ is cyano, —COR¹⁶ or —SO₂R¹⁶; R¹⁹ is: (a) hydrogen, (b)(C₁-C₆)-alkyl, (c) —CO(C₁-C₆)-alkyl, (d) —CO(C₁-C₆)-aryl, (e)—CO(C₁-C₆)-heteroaryl, (f) —CO₂(C₁-C₆)-alkyl, (g) CO₂(C₁-C₆)-aryl, (h)CO₂(C₁-C₆)-heteroaryl, (i) —CONR⁸R⁹, (j) —S(O)_(n)-alkyl, (k)—S(O)_(n)-aryl, (l) —S(O)_(n)-heteroaryl, or (m) —S(O)_(n)—NR⁸R⁹; R²⁰ isindependently: (a) hydrogen, (b) halo, (c) —OH, (d)—O[(C═O)O_(r)]_(s)(C₁-C₆)-alkyl, (e) —O[(C═O)O_(r)]_(s)(C₂-C₆)-alkenyl,(f) —O[(C═O)O_(r)]_(s)aryl, (g) —O[(C═O)O_(r)]_(s)heteroaryl, (h)(C₁-C₆)-alkyl-S(O)_(n)—, (i) aryl-(C₁-C₆)alkyloxy-, (j) cyano, (k)nitro, (l) —NR⁸R⁹ (m) O(CO)NR⁸R⁹, (n) —CHO, (o) COOH, (p)—CO(C₁-C₆)-alkyl, (q) —CO₂(C₁-C₆)-alkyl, (r) —CONR⁸R⁹, (s) aryl, whichmay optionally be substituted with one or more substituents selectedfrom the group consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, 4)(C₁-C₄)-perfluoroalkyl, 5) (C₂-C₆)-alkenyl, 6) (C₂-C₆)-alkynyl, 7)(C₁-C₆)-alkyloxy, 8) (C₁-C₆)-alkyl-S(O)_(n)—, 9) cyano, 10) —COOH, 11)—CO(C₁-C₆)-alkyl, 12) —CO₂(C₁-C₆)-alkyl, 13) —CONR⁸R⁹, 14) —NR⁸R⁹, 15)—O(C═O)—(C₁-C₆)-alkyl, and 16) —O(C═O)NR⁸R⁹, (t) heteroaryl optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, 4)(C₁-C₄)-perfluoroalkyl, 5) (C₂-C₆)-alkenyl, 6) (C₂-C₆)-alkynyl, 7)(C₁-C₆)-alkyloxy, 8) (C₁-C₆)-alkyl-S(O)_(n)—, 9) cyano, 10) —COOH, 11)—CO(C₁-C₆)-alkyl, 12) —CO₂(C₁-C₆)-alkyl, 13) —CONR⁸R⁹, 14) —NR⁸R⁹, 15)—O(C═O)—(C₁-C₆)-alkyl, and 16) —O(C═O)NR⁸R⁹, (u) heterocyclo other thanheteroaryl which is optionally substituted with one or more substituentsselected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, 4) (C₁-C₄)-perfluoroalkyl, 5) (C₂-C₆)-alkenyl, 6)(C₂-C₆)-alkynyl, 7) (C₁-C₆)-alkyloxy, 8) (C₁-C₆)-alkyl-S(O)_(n)—, 9)cyano, 10) —COOH, 11) —CO(C₁-C₆)-alkyl, 12) —CO₂(C₁-C₆)-alkyl, 13)—CONR⁸R⁹, 14) —NR⁸R⁹, 15) —O(C═O)—(C₁-C₆)-alkyl, and 16) —O(C═O)NR⁸R⁹,(v) benzyl-S(O)_(n)—, (w) (C₂-C₁₀)-alkenyl, which may optionally besubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) cyano, 6) —COOH, 7) —CO(C₁-C₆)-alkyl, 8)—CO₂(C₁-C₆)-alkyl, 9) —CONR⁸R⁹, 10) —NR⁸R⁹, 11) —O(C═O)—(C₁-C₆)-alkyl,and 12) —O(C═O)NR⁸R⁹, (x) (C₂-C₁₀)-alkynyl wherein alkynyl is optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) cyano, 6) —COOH, 7) —CO(C₁-C₆)-alkyl, 8)—CO₂(C₁-C₆)-alkyl, 9) —CONR⁸R⁹, 10) —NR⁸R⁹, 11) —O(C═O)—(C₁-C₆)-alkyl,and 12) —O(C═O)NR⁸R⁹, (y) —(C₁-C₁₀)-alkyl, which may optionally besubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) benzyl-S(O)_(n)—, 6) cyano, 7) —COOH, 8)—CO(C₁-C₆)-alkyl, 9) —CO₂(C₁-C₆)-alkyl, 10) —CONR⁸R⁹, 11) —NR⁸R⁹, 12)—O(C═O)—(C₁-C₆)-alkyl, and 13) —O(C═O)NR⁸R⁹; R²¹ is: (a) C₁-C₁₀-alkyloptionally substituted with one or more R¹¹'s, (b) C₃-C₈-cycloalkyloptionally substituted with one or more R¹¹'s, (c) aryl optionallysubstituted with one or more R¹¹'s, or (d) heterocyclyl optionallysubstituted with one or more R¹¹'s; m is 1 to 5; n is 0 to 3; p is 1 or2; r is 0 to 5; and s is 0 to
 4. 19. A method of controlling heart ratecomprising administering to a patient in need thereof an effectiveamount of at least one compound of formula I

or a stereoisomer or a tautomer or a pharmaceutically acceptable salt ora prodrug thereof, wherein: R¹ is an aryl or heterocyclic ring, whichmay be optionally substituted with one or more R¹⁰'s; R² and R³ areindependently: (a) halo, (b) (C₁-C₆)-alkoxy optionally substituted withone or more R's, (c) (C₁-C₄)-perfluoroalkyl, (d)(C₁-C₆)-alkyl-S(O)_(n)—, (e) aryl-(CH₂)_(r)—S(O)_(n)—, (f) cyano, (g)—CO₂H, (h) —CO(C₁-C₆)-alkyl, (i) —CO₂(C₁-C₆)-alkyl, (j) —CONR⁸R⁹, (k)—O(CO)NR⁸R⁹, (l) —NR⁸(CO)NR⁸R⁹, (m) —NR⁸R⁹, (n) hydrogen, (o)C₁-C₁₀-alkyl optionally substituted with one or more R¹¹'s, (p)(C₂-C₁₀)-alkenyl optionally substituted with one or more R¹¹'s, (q)(C₂-C₁₀)-alkynyl optionally substituted with one or more R¹¹'s, (r) aryloptionally substituted with one or more R¹¹'s, (s) heterocyclyloptionally substituted with one or more R¹¹'s, or (t) —NR⁸(CO)OR²,provided that both R² and R³ are not simultaneously hydrogen; R⁴ is: (a)hydrogen, (b) C₁-C₁₀-alkyl, (c) —CO(C₁-C₆)-alkyl, (d) —COaryl, (e)—COheterocyclyl, (f) —CO₂(C₁-C₆)-alkyl, (g) —CO₂aryl, (h)—CO₂heterocyclyl, (i) —CONR⁸R⁹, (j) —S(O)_(n)-alkyl, (k) —S(O)_(n)-aryl,(l) —S(O)_(n)-heterocyclyl, or (m) —S(O)_(n)—NR⁸R⁹; R⁵ is

wherein the dashed line(s) represent an optional double bond; T is O, S,C═O, N, NR¹⁹ or C(R²⁰)_(p); Q, X, U, V and W are independently O, S,C═O, N, NR¹⁹ or C(R²⁰)_(p), provided that Q is not C(R²⁰)_(p) when X isN or NR¹⁹; R⁸ and R⁹ are independently: (a) hydrogen, (b)—[(C═O)O_(r)]_(s)aryl, wherein the aryl may be optionally substitutedwith one or more R¹⁴'s, (c) —[(C═O)O_(r)]_(s)(C₂-C₈)-alkenyl, whereinthe alkenyl may be optionally substituted with one or more R¹⁴'s, (d)—[(C═O)O_(r)]_(s)(C₁-C₈)alkyl, wherein the alkyl may be optionallysubstituted with one or more R¹⁴'s, (e) —S(O)_(p)(C₁-C₈)alkyl, whereinthe alkyl may be optionally substituted with one or more R¹⁴'s, (f)—S(O)_(p)NR¹⁶R¹⁷, (g) —C(═NR¹⁸)(NR¹⁶R¹⁷), or (h) heterocyclyl optionallysubstituted with one or more R¹⁴'s, or R⁸ and R⁹ are taken together withthe nitrogen to which both are attached to form a 3- to 8-membered ring,which may optionally contain 1-4 heteroatoms selected from N, O, and Sand be optionally substituted with one or more R¹⁴'s; R¹⁰ is: (a) halo,(b) —OH, (c) —O[(C═O)O_(r)]_(s)(C₁-C₆)-alkyl, (d)—O[(C═O)O_(r)]_(s)(C₂-C₆)-alkenyl, (e) —O[(C═O)O_(r)]_(s)aryl, (f)—O[(C═O)O_(r)]_(s)heteroaryl, (g) (C₁-C₆)-alkyl-S(O)_(n)—, (h)aryl-(C₁-C₆)alkyloxy-, (i) cyano, (j) nitro, (k) —NR⁸R⁹, (l)—O(CO)NR⁸R⁹, (m) —CHO, (n) —COOH, (o) —CO(C₁-C₆)-alkyl, (p)—CO₂(C₁-C₆)-alkyl, (q) —CONR⁸R⁹, (r) aryl, which may optionally besubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, 4)(C₁-C₄)-perfluoroalkyl, 5) (C₂-C₆)-alkenyl, 6) (C₂-C₆)-alkynyl, 7)(C₁-C₆)-alkyloxy, 8) (C₁-C₆)-alkyl-S(O)_(n)—, 9) cyano, 10) —COOH, 11)—CO(C₁-C₆)-alkyl, 12) —CO₂(C₁-C₆)-alkyl, 13) —CONR⁸R⁹, 14) —NR⁸R⁹, 15)—O(C═O)—(C₁-C₆)-alkyl, and 16) —O(C═O)NR⁸R⁹, (s) heteroaryl optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, 4)(C₁-C₄)-perfluoroalkyl, 5) (C₂-C₆)-alkenyl, 6) (C₂-C₆)-alkynyl, 7)(C₁-C₆)-alkyloxy, 8) (C₁-C₆)-alkyl-S(O)_(n)—, 9) cyano, 10) —COOH, 11)—CO(C₁-C₆)-alkyl, 12) —CO₂(C₁-C₆)-alkyl, 13) —CONR⁸R⁹, 14) —NR⁸R⁹, 15)—O(C═O)—(C₁-C₆)-alkyl, and 16) —O(C═O)NR⁸R⁹, (t) heterocyclo other thanheteroaryl which is optionally substituted with one or more substituentsselected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, 4) (C₁-C₄)-perfluoroalkyl, 5) (C₂-C₆)-alkenyl, 6)(C₂-C₆)-alkynyl, 7) (C₁-C₆)-alkyloxy, 8) (C₁-C₆)-alkyl-S(O)_(n)—, 9)cyano, 10) —COOH, 11) —CO(C₁-C₆)-alkyl, 12) —CO₂(C₁-C₆)-alkyl, 13)—CONR⁸R⁹, 14) —NR⁸R⁹, 15) —O(C═O)—(C₁-C₆)-alkyl, and 16) —O(C═O)NR⁸R⁹,(u) benzyl-S(O)_(n)—, (v) (C₂-C₁₀)-alkenyl, which may optionally besubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) cyano, 6) —COOH, 7) —CO(C₁-C₆)-alkyl, 8)—CO₂(C₁-C₆)-alkyl, 9) —CONR⁸R⁹, 10) —NR⁸R⁹, 11) —O(C═O)—(C₁-C₆)-alkyl,and 12) —O(C═O)NR⁸R⁹, (w) (C₂-C₁₀)-alkynyl wherein alkynyl is optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) cyano, 6) —COOH, 7) —CO(C₁-C₆)-alkyl, 8)—CO₂(C₁-C₆)-alkyl, 9) —CONR⁸R⁹, 10) —NR⁸R⁹, 11) —O(C═O)—(C₁-C₆)-alkyl,and 12) —O(C═O)NR⁸R⁹, (x) —(C₁-C₁₀)-alkyl, which may optionally besubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) benzyl-S(O)_(n)—, 6) cyano, 7) —COOH, 8)—CO(C₁-C₆)-alkyl, 9) —CO₂(C₁-C₆)-alkyl, 10) —CONR⁸R⁹, 11) —NR⁸R⁹, 12)—O(C═O)—(C₁-C₆)-alkyl, and 13) —O(C═O)NR⁸R⁹; R¹¹ is: (a) halo, (b) —OH,(c) —O[(C═O)O_(r)]_(s)(C₁-C₆)-alkyl, (d)—O[(C═O)O_(r)]_(s)(C₂-C₆)-alkenyl, (e) —O[(C═O)O_(r)]_(s)aryl, (f)—O[(C═O)O_(r)]_(s)heteroaryl, (g) (C₁-C₆)-alkyl-S(O)_(n)—, (h)aryl-(C₁-C₆)alkyloxy-, (i) cyano, (j) —NR⁸R⁹, (k) —O(CO)NR⁸R⁹, (l)—COOH, (m) —CO(C₁-C₆)-alkyl, (n) —CO₂(C₁-C₆)-alkyl, (o) —CONR⁸R⁹, (p)aryl, which may optionally be substituted with one or more substituentsselected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, 4) aryl-(C₁-C₆)alkyloxy-, 5) (C₁-C₄)-perfluoroalkyl, 6)(C₂-C₆)-alkenyl, 7) (C₂-C₆)-alkynyl, 8) (C₁-C₆)-alkyloxy, 9)(C₁-C₆)-alkyl-S(O)_(n)—, 10) cyano, 11) —COOH, 12) —CO(C₁-C₆)-alkyl, 13)—CO₂(C₁-C₆)-alkyl, 14) —CONR⁸R⁹, 15) —NR⁸R⁹, 16) —O(C═O)—(C₁-C₆)-alkyl,and 17) —O(C═O)NR⁸R⁹, (q) heteroaryl optionally substituted with one ormore substituents selected from the group consisting of: 1) halo, 2)—OH, 3) (C₁-C₆)-alkyl, 4) aryl-(C₁-C₆)alkyloxy-, 5)(C₁-C₄)-perfluoroalkyl, 6) (C₂-C₆)-alkenyl, 7) (C₂-C₆)-alkynyl, 8)(C₁-C₆)-alkyloxy, 9) (C₁-C₆)-alkyl-S(O)_(n)—, 10) cyano, 11) —COOH, 12)—CO(C₁-C₆)-alkyl, 13) —CO₂(C₁-C₆)-alkyl, 14) —CONR⁸R⁹, 15) —NR⁸R⁹, 16)—O(C═O)—(C₁-C₆)-alkyl, and 17) —O(C═O)NR⁸R⁹, (r) heterocyclo other thanheteroaryl which is optionally substituted with one or more substituentsselected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, 4) aryl-(C₁-C₆)alkyloxy-, 5) (C₁-C₄)-perfluoroalkyl, 6)(C₂-C₆)-alkenyl, 7) (C₂-C₆)-alkynyl, 8) (C₁-C₆)-alkyloxy, 9)(C₁-C₆)-alkyl-S(O)_(n)—, 10) cyano, 11) —COOH, 12) —CO(C₁-C₆)-alkyl, 13)—CO₂(C₁-C₆)-alkyl, 14) —CONR⁸R⁹, 15) —NR⁸R⁹, 16) —O(C═O)—(C₁-C₆)-alkyl,and 17) — (C═O)NR⁸R⁹, (s) —(C₂-C₁₀)-alkenyl, which may optionally besubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) phenyl-(C₁-C₆)-alkyloxy-, 6) cyano, 7) —CHO,8) —COOH, 9) —CO(C₁-C₆)-alkyl, 10) —CO₂(C₁-C₆)-alkyl, 11) —CONR⁸R⁹, 12)—NR⁸R⁹, 13) aryl, 14) heteroaryl as defined above, 15) heterocyclo otherthan heteroaryl as defined above, 16) —O(C═O)—(C₁-C₆)-alkyl, and 17)—O(C═O)NR⁸R⁹, (t) (C₂-C₁₀)-alkynyl wherein alkynyl is optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) phenyl-(C₁-C₆)-alkyloxy-, 6) cyano, 7)vinyl, 8) —CHO, 9) —COOH, 10) —CO(C₁-C₆)-alkyl, 11) —CO₂(C₁-C₆)-alkyl,12) —CONR⁸R⁹, 13) —NR⁸R⁹, 14) aryl, wherein aryl is defined as above,15) heteroaryl as defined above, 16) heterocyclyl other than heteroarylas defined above, 17) —O(C═O)—(C₁-C₆)-alkyl, and 18) —O(C═O)NR⁸R⁹, (u)—(C₁-C₁₀)-alkyl, which may optionally be substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyloxy, 4) (C₁-C₆)-alkyl-S(O)_(n)—, 5) benzyl-S(O)_(n)—, 6)cyano, 7) —COOH, 8) —CO(C₁-C₆)-alkyl, 9) —CO₂(C₁-C₆)-alkyl, 10)—CONR⁸R⁹, 11) —NR⁸R⁹, 12) —O(C═O)—(C₁-C₆)-alkyl, and 13) —O(C═O)NR⁸R⁹,(v) —O(CH₂)_(m)-heteroaryl as defined above; R¹² is: (a) halo, (b) —OH,(c) —O[(C═O)O_(r)]_(s)(C₁-C₆)-alkyl, (d)—O[(C═O)O_(r)]_(s)(C₂-C₆)-alkenyl, (e) —O[(C═O)O_(r)]_(s)aryl, (f)—O[(C═O)O_(r)]_(s)heteroaryl, (g) (C₁-C₆)-alkyl-S(O)_(n)—, (h)aryl-(C₁-C₆)alkyloxy-, (i) cyano, (j) nitro, (k) —NR⁸R⁹, (l)—O(CO)NR⁸R⁹, (m) —CHO, (n) —COOH, (o) —CO(C₁-C₆)-alkyl, (p)—CO₂(C₁-C₆)-alkyl, (q) —CONR⁸R⁹, (r) aryl, which may optionally besubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, 4)(C₁-C₄)-perfluoroalkyl, 5) (C₂-C₆)-alkenyl, 6) (C₂-C₆)-alkynyl, 7)(C₁-C₆)-alkyloxy, 8) (C₁-C₆)-alkyl-S(O)_(n)—, 9) cyano, 10) —COOH, 11)—CO(C₁-C₆)-alkyl, 12) —CO₂(C₁-C₆)-alkyl, 13) —CONR⁸R⁹, 14) —NR⁸R⁹, 15)—O(C═O)—(C₁-C₆)-alkyl, and 16) —O(C═O)NR⁸R⁹, (s) heteroaryl optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, 4)(C₁-C₄)-perfluoroalkyl, 5) (C₂-C₆)-alkenyl, 6) (C₂-C₆)-alkynyl, 7)(C₁-C₆)-alkyloxy, 8) (C₁-C₆)-alkyl-S(O)_(n)—, 9) cyano, 10) —COOH, 11)—CO(C₁-C₆)-alkyl, 12) —CO₂(C₁-C₆)-alkyl, 13) —CONR⁸R⁹, 14) —NR⁸R⁹, 15)—O(C═O)—(C₁-C₆)-alkyl, and 16) —O(C═O)NR⁸R⁹, (t) heterocyclo other thanheteroaryl which is optionally substituted with one or more substituentsselected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, 4) (C₁-C₄)-perfluoroalkyl, 5) (C₂-C₆)-alkenyl, 6)(C₂-C₆)-alkynyl, 7) (C₁-C₆)-alkyloxy, 8) (C₁-C₆)-alkyl-S(O)_(n)—, 9)cyano, 10) —COOH, 11) —CO(C₁-C₆)-alkyl, 12) —CO₂(C₁-C₆)-alkyl, 13)—CONR⁸R⁹, 14) —NR⁸R⁹, 15) —O(C═O)—(C₁-C₆)-alkyl, and 16) —O(C═O)NR⁸R⁹,(u) benzyl-S(O)_(n)—, (v) (C₂-C₁₀)-alkenyl, which may optionally besubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)(C₁-C₆)-alkyl-S(O)_(r)—, 5) cyano, 6) —COOH, 7) —CO(C₁-C₆)-alkyl, 8)—CO₂(C₁-C₆)-alkyl, 9) —CONR⁸R⁹, 10) —NR⁸R⁹, 11) —O(C═O)—(C₁-C₆)-alkyl,and 12) —O(C═O)NR⁸R⁹, (w) (C₂-C₁₀)-alkynyl wherein alkynyl is optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) cyano, 6) —COOH, 7) —CO(C₁-C₆)-alkyl, 8)—CO₂(C₁-C₆)-alkyl, 9) —CONR⁸R⁹, 10) —NR⁸R⁹, 11) —O(C═O)—(C₁-C₆)-alkyl,and 12) —O(C═O)NR⁸R⁹, (x) —(C₁-C₁₀)-alkyl, which may optionally besubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) benzyl-S(O)_(n)—, 6) cyano, 7) —COOH, 8)—CO(C₁-C₆)-alkyl, 9) —CO₂(C₁-C₆)-alkyl, 10) —CONR⁸R⁹, 11) —NR⁸R⁹, 12)—O(C═O)—(C₁-C₆)-alkyl, and 13) —O(C═O)NR⁸R⁹, (y) ═O; R¹⁴ is: (a) halo,(b) —OH, (c) —O[(C═O)O_(r)]_(s)(C₁-C₆)-alkyl, (d)—O[(C═O)O_(r)]_(s)(C₂-C₆)-alkenyl, (e) —O[(C═O)O_(r)]_(s)aryl, (f)—O[(C═O)O_(r)]_(s)heteroaryl, (g) (C₁-C₆)-alkyl-S(O)_(n)—, (h)aryl-(C₁-C₆)alkyloxy-, (i) cyano, (j) nitro, (k) —NR⁸R⁹, (l)—O(CO)NR⁸R⁹, (m) —CHO, (n) —COOH, (o) —CO(C₁-C₆)-alkyl, (p)—CO₂(C₁-C₆)-alkyl, (q) —CONR⁸R⁹, (r) aryl, which may optionally besubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, 4)(C₁-C₄)-perfluoroalkyl, 5) (C₂-C₆)-alkenyl, 6) (C₂-C₆)-alkynyl, 7)(C₁-C₆)-alkyloxy, 8) (C₁-C₆)-alkyl-S(O)_(n)—, 9) cyano, 10) —COOH, 11)—CO(C₁-C₆)-alkyl, 12) —CO₂(C₁-C₆)-alkyl, 13) —CONR⁸R⁹, 14) —NR⁸R⁹, 15)—O(C═O)—(C₁-C₆)-alkyl, and 16) —O(C═O)NR⁸R⁹, (s) heteroaryl optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, 4)(C₁-C₄)-perfluoroalkyl, 5) (C₂-C₆)-alkenyl, 6) (C₂-C₆)-alkynyl, 7)(C₁-C₆)-alkyloxy, 8) (C₁-C₆)-alkyl-S(O)_(n)—, 9) cyano, 10) —COOH, 11)—CO(C₁-C₆)-alkyl, 12) —CO₂(C₁-C₆)-alkyl, 13) —CONR⁸R⁹, 14) —NR⁸R⁹, 15)—O(C═O)—(C₁-C₆)-alkyl, and 16) —O(C═O)NR⁸R⁹, (t) heterocyclo other thanheteroaryl which is optionally substituted with one or more substituentsselected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, 4) (C₁-C₄)-perfluoroalkyl, 5) (C₂-C₆)-alkenyl, 6)(C₂-C₆)-alkynyl, 7) (C₁-C₆)-alkyloxy, 8) (C₁-C₆)-alkyl-S(O)_(n)—, 9)cyano, 10) —COOH, 11) —CO(C₁-C₆)-alkyl, 12) —CO₂(C₁-C₆)-alkyl, 13)—CONR⁸R⁹, 14) —NR⁸R⁹, 15) —O(C═O)—(C₁-C₆)-alkyl, and 16) —O(C═O)NR⁸R⁹,(u) benzyl-S(O)_(n)—, (v) (C₂-C₁₀)-alkenyl, which may optionally besubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) cyano, 6) —COOH, 7) —CO(C₁-C₆)-alkyl, 8)—CO₂(C₁-C₆)-alkyl, 9) —CONR⁸R⁹, 10) —NR⁸R⁹, 11) —O(C═O)—(C₁-C₆)-alkyl,and 12) —O(C═O)NR⁸R⁹, (w) (C₂-C₁₀)-alkynyl wherein alkynyl is optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) cyano, 6) —COOH, 7) —CO(C₁-C₆)-alkyl, 8)—CO₂(C₁-C₆)-alkyl, 9) —CONR⁸R⁹, 10) —NR⁸R⁹, 11) —O(C═O)—(C₁-C₆)-alkyl,and 12) —O(C═O)NR⁸R⁹, (x) —(C₁-C₁₀)-alkyl, which may optionally besubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) benzyl-S(O)_(n)—, 6) cyano, 7) —COOH, 8)—O(C₁-C₆)-alkyl, 9) —CO₂(C₁-C₆)-alkyl, 10) —CONR⁸R⁹, 11) —NR⁸R⁹, 12)—O(C═O)—(C₁-C₆)-alkyl, and 13) —O(C═O)NR⁸R⁹; R¹⁶ and R¹⁷ areindependently: (a) aryl, which may optionally be substituted with one ormore substituents selected from the group consisting of: 1) halo, 2)—OH, 3) (C₁-C₆)-alkyl, 4) (C₁-C₄)-perfluoroalkyl, 5) (C₂-C₆)-alkenyl, 6)(C₂-C₆)-alkynyl, 7) (C₁-C₆)-alkyloxy, 8) (C₁-C₆)-alkyl-S(O)_(n)—, 9)cyano, 10) —COOH, 11) —CO(C₁-C₆)-alkyl, 12) —CO₂(C₁-C₆)-alkyl, 13)—CONR⁸R⁹, 14) —NR⁸R⁹, 15) —O(C═O)—(C₁-C₆)-alkyl, and 16) —O(C═O)NR⁸R⁹,(b) heteroaryl optionally substituted with one or more substituentsselected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, 4) (C₁-C₄)-perfluoroalkyl, 5) (C₂-C₆)-alkenyl, 6)(C₂-C₆)-alkynyl, 7) (C₁-C₆)-alkyloxy, 8) (C₁-C₆)-alkyl-S(O)_(n)—, 9)cyano, 10) —COOH, 11) —CO(C₁-C₆)-alkyl, 12) —CO₂(C₁-C₆)-alkyl, 13)—CONR⁸R⁹, 14) —NR⁸R⁹, 15) —O(C═O)—(C₁-C₆)-alkyl, and 16) —O(C═O)NR⁸R⁹,(c) heterocyclo other than heteroaryl which is optionally substitutedwith one or more substituents selected from the group consisting of: 1)halo, 2) —OH, 3) (C₁-C₆)-alkyl, 4) (C₁-C₄)-perfluoroalkyl, 5)(C₂-C₆)-alkenyl, 6) (C₂-C₆)-alkynyl, 7) (C₁-C₆)-alkyloxy, 8)(C₁-C₆)-alkyl-S(O)_(n)—, 9) cyano, 10) —COOH, 11) —CO(C₁-C₆)-alkyl, 12)—CO₂(C₁-C₆)-alkyl, 13) —CONR⁸R⁹, 14) —NR⁸R⁹, 15) —O(C═O)—(C₁-C₆)-alkyl,and 16) —O(C═O)NR⁸R⁹, (d) (C₂-C₁₀)-alkenyl, which may optionally besubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) cyano, 6) —COOH, 7) —CO(C₁-C₆)-alkyl, 8)—CO₂(C₁-C₆)-alkyl, 9) —CONR⁸R⁹, 10) —NR⁸R⁹, 11) —O(C═O)—(C₁-C₆)-alkyl,and 12) —O(C═O)NR⁸R⁹, (e) (C₂-C₁₀)-alkynyl wherein alkynyl is optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) cyano, 6) —COOH, 7) —CO(C₁-C₆)-alkyl, 8)—CO₂(C₁-C₆)-alkyl, 9) —CONR⁸R⁹, 10) —NR⁸R⁹, 11) —O(C═O)—(C₁-C₆)-alkyl,and 12) —O(C═O)NR⁸R⁹, (f) —(C₁-C₁₀)-alkyl, which may optionally besubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) benzyl-S(O)_(n)—, 6) cyano, 7) —COOH, 8)—CO(C₁-C₆)-alkyl, 9) —CO₂(C₁-C₆)-alkyl, 10) —CONR⁸R⁹, 11) —NR⁸R⁹, 12)—O(C═O)—(C₁-C₆)-alkyl, and 13) —O(C═O)NR⁸R⁹, or R¹⁶ and R¹⁷ are takentogether with the nitrogen to which both are attached to form a 3- to8-membered ring, which may optionally contain 1-4 heteroatoms selectedfrom N, O, and S and be optionally substituted with one or more R¹⁴'s;R¹⁸ is cyano, —COR¹⁶ or —SO₂R¹⁶; R¹⁹ is: (a) hydrogen, (b)(C₁-C₆)-alkyl, (c) —CO(C₁-C₆)-alkyl, (d) —CO(C₁-C₆)-aryl, (e)—CO(C₁-C₆)-heteroaryl, (f) —CO₂(C₁-C₆)-alkyl, (g) CO₂(C₁-C₆)-aryl, (h)CO₂(C₁-C₆)-heteroaryl, (i) —CONR⁸R⁹, (j) —S(O)_(n)-alkyl, (k)—S(O)_(n)-aryl, (l) —S(O)_(n)-heteroaryl, or (m) —S(O)_(n)—NR⁸R⁹; R²⁰ isindependently: (a) hydrogen, (b) halo, (c) —OH, (d)—O[(C═O)O_(r)]_(s)(C₁-C₆)-alkyl, (e) —O[(C═O)O_(r)]_(s)(C₂-C₆)-alkenyl,(f) —O[(C═O)O_(r)]_(s)aryl, (g) —O[(C═O)O_(r)]_(s)heteroaryl, (h)(C₁-C₆)-alkyl-S(O)_(n)—, (i) aryl-(C₁-C₆)alkyloxy-, 0) cyano, (k) nitro,(l) —NR⁸R⁹ (m) O(CO)NR⁸R⁹, (n) —CHO, (o) COOH, (p) —CO(C₁-C₆)-alkyl, (q)—CO₂(C₁-C₆)-alkyl, (r) —CONR⁸R⁹, (s) aryl, which may optionally besubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, 4)(C₁-C₄)-perfluoroalkyl, 5) (C₂-C₆)-alkenyl, 6) (C₂-C₆)-alkynyl, 7)(C₁-C₆)-alkyloxy, 8) (C₁-C₆)-alkyl-S(O)_(n)—, 9) cyano, 10) —COOH, 11)—CO(C₁-C₆)-alkyl, 12) —CO₂(C₁-C₆)-alkyl, 13) —CONR⁸R⁹, 14) —NR⁸R⁹, 15)—O(C═O)—(C₁-C₆)-alkyl, and 16) —O(C═O)NR⁸R⁹, (t) heteroaryl optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, 4)(C₁-C₄)-perfluoroalkyl, 5) (C₂-C₆)-alkenyl, 6) (C₂-C₆)-alkynyl, 7)(C₁-C₆)-alkyloxy, 8) (C₁-C₆)-alkyl-S(O)_(n)—, 9) cyano, 10) —COOH, 11)—CO(C₁-C₆)-alkyl, 12) —CO₂(C₁-C₆)-alkyl, 13) —CONR⁸R⁹, 14) —NR⁸R⁹, 15)—O(C═O)—(C₁-C₆)-alkyl, and 16) —O(C═O)NR⁸R⁹, (u) heterocyclo other thanheteroaryl which is optionally substituted with one or more substituentsselected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, 4) (C₁-C₄)-perfluoroalkyl, 5) (C₂-C₆)-alkenyl, 6)(C₂-C₆)-alkynyl, 7) (C₁-C₆)-alkyloxy, 8) (C₁-C₆)-alkyl-S(O)_(n)—, 9)cyano, 10) —COOH, 11) —CO(C₁-C₆)-alkyl, 12) —CO₂(C₁-C₆)-alkyl, 13)—CONR⁸R⁹, 14) —NR⁸R⁹, 15) —O(C═O)—(C₁-C₆)-alkyl, and 16) —O(C═O)NR⁸R⁹,(v) benzyl-S(O)_(n)—, (w) (C₂-C₁₀)-alkenyl, which may optionally besubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) cyano, 6) —COOH, 7) —CO(C₁-C₆)-alkyl, 8)—CO₂(C₁-C₆)-alkyl, 9) —CONR⁸R⁹, 10) —NR⁸R⁹, 11) —O(C═O)—(C₁-C₆)-alkyl,and 12) —O(C═O)NR⁸R⁹, (x) (C₂-C₁₀)-alkynyl wherein alkynyl is optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) cyano, 6) —COOH, 7) —CO(C₁-C₆)-alkyl, 8)—CO₂(C₁-C₆)-alkyl, 9) —CONR⁸R⁹, 10) —NR⁸R⁹, 11) —O(C═O)—(C₁-C₆)-alkyl,and 12) —O(C═O)NR⁸R⁹, (y) —(C₁-C₁₀)-alkyl, which may optionally besubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) benzyl-S(O)_(n)—, 6) cyano, 7) —COOH, 8)—CO(C₁-C₆)-alkyl, 9) —CO₂(C₁-C₆)-alkyl, 10) —CONR⁸R⁹, 11) —NR⁸R⁹, 12)—O(C═O)—(C₁-C₆)-alkyl, and 13) —O(C═O)NR⁸R⁹; R²¹ is: (a) C₁-C₁₀-alkyloptionally substituted with one or more R¹¹'s, (b) C₃-C₈-cycloalkyloptionally substituted with one or more R¹¹'s, (c) aryl optionallysubstituted with one or more R¹¹'s, or (d) heterocyclyl optionallysubstituted with one or more R¹¹'s; m is 1 to 5; n is 0 to 3; p is 1 or2; r is 0 to 5; and s is 0 to
 4. 20. A method of treating anI_(Kur)-associated condition comprising administering to a patient inneed thereof an effective amount of at least one compound of formula I

or a stereoisomer or a tautomer or a pharmaceutically acceptable salt ora prodrug thereof, wherein: R¹ is an aryl or heterocyclic ring, whichmay be optionally substituted with one or more R¹⁰'s; R² and R³ areindependently: (a) halo, (b) (C₁-C₆)-alkoxy optionally substituted withone or more R¹¹'s, (c) (C₁-C₄)-perfluoroalkyl, (d)(C₁-C₆)-alkyl-S(O)_(n)—, (e) aryl-(CH₂)_(r)—S(O)_(n)—, (f) cyano, (g)—CO₂H, (h) —CO(C₁-C₆)-alkyl, (i) —CO₂(C₁-C₆)-alkyl, (j) —CONR⁸R⁹, (k)—O(CO)NR⁸R⁹, (l) —NR⁸(CO)NR⁸R⁹, (m) —NR⁸R⁹, (n) hydrogen, (o)C₁-C₁₀-alkyl optionally substituted with one or more R¹¹'s, (p)(C₂-C₁₀)-alkenyl optionally substituted with one or more R¹¹'s, (q)(C₂-C₁₀)-alkynyl optionally substituted with one or more R¹¹'s, (r) aryloptionally substituted with one or more R¹¹'s, (s) heterocyclyloptionally substituted with one or more R¹¹'s, or (t) —NR⁸(CO)OR²¹,provided that both R² and R³ are not simultaneously hydrogen; R⁴ is: (a)hydrogen, (b) C₁-C₁₀-alkyl, (c) —CO(C₁-C₆)-alkyl, (d) —COaryl, (e)—COheterocyclyl, (f) —CO₂(C₁-C₆)-alkyl, (g) —CO₂aryl, (h)—CO₂heterocyclyl, (i) —CONR⁸R⁹, (j) —S(O)_(n)-alkyl, (k) —S(O)_(n)-aryl,(l) —S(O)_(n)-heterocyclyl, or (m) —S(O)_(n)—NR⁸R⁹; R⁵ is

wherein the dashed line(s) represent an optional double bond; T is O, S,C═O, N, NR¹⁹ or C(R²⁰)_(p); Q, X, U, V and W are independently O, S,C═O, N, NR¹⁹ or C(R²⁰)_(p), provided that Q is not C(R²⁰)_(p) when X isN or NR¹⁹; R⁸ and R⁹ are independently: (a) hydrogen, (b)—[(C═O)O_(r)]_(s)aryl, wherein the aryl may be optionally substitutedwith one or more R¹⁴'s, (c) —[(C═O)O_(r)]_(s)(C₂-C₈)-alkenyl, whereinthe alkenyl may be optionally substituted with one or more R¹⁴'s, (d)—[(C═O)O_(r)]_(s)(C₁-C₈)alkyl, wherein the alkyl may be optionallysubstituted with one or more R¹⁴'s, (e) —S(O)_(p)(C₁-C₈)alkyl, whereinthe alkyl may be optionally substituted with one or more R¹⁴, (f)—S(O)_(p)NR¹⁶R¹⁷, (g) —C(═NR¹⁸)(NR¹⁶R¹⁷), or (h) heterocyclyl optionallysubstituted with one or more R¹⁴'s, or R⁸ and R⁹ are taken together withthe nitrogen to which both are attached to form a 3- to 8-membered ring,which may optionally contain 1-4 heteroatoms selected from N, O, and Sand be optionally substituted with one or more R¹⁴'s; R¹⁰ is: (a) halo,(b) —OH, (c) —O[(C═O)O_(r)]_(s)(C₁-C₆)-alkyl, (d)—O[(C═O)O_(r)]_(s)(C₂-C₆)-alkenyl, (e) —O[(C═O)O_(r)]_(s)aryl, (f)—O[(C═O)O_(r)]_(s)heteroaryl, (g) (C₁-C₆)-alkyl-S(O)_(n)—, (h)aryl-(C₁-C₆)alkyloxy-, (i) cyano, (j) nitro, (k) —NR⁸R⁹, (l)—O(CO)NR⁸R⁹, (m) —CHO, (n) —COOH, (o) —CO(C₁-C₆)-alkyl, (p)—CO₂(C₁-C₆)-alkyl, (q) —CONR⁸R⁹, (r) aryl, which may optionally besubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, 4)(C₁-C₄)-perfluoroalkyl, 5) (C₂-C₆)-alkenyl, 6) (C₂-C₆)-alkynyl, 7)(C₁-C₆)-alkyloxy, 8) (C₁-C₆)-alkyl-S(O)_(n)—, 9) cyano, 10) —COOH, 11)—CO(C₁-C₆)-alkyl, 12) —CO₂(C₁-C₆)-alkyl, 13) —CONR⁸R⁹, 14) —NR⁸R⁹, 15)—O(C═O)—(C₁-C₆)-alkyl, and 16) —O(C═O)NR⁸R⁹, (s) heteroaryl optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, 4)(C₁-C₄)-perfluoroalkyl, 5) (C₂-C₆)-alkenyl, 6) (C₂-C₆)-alkynyl, 7)(C₁-C₆)-alkyloxy, 8) (C₁-C₆)-alkyl-S(O)_(n)—, 9) cyano, 10) —COOH, 11)—CO(C₁-C₆)-alkyl, 12) —CO₂(C₁-C₆)-alkyl, 13) —CONR⁸R⁹, 14) —NR⁸R⁹, 15)—O(C═O)—(C₁-C₆)-alkyl, and 16) —O(C═O)NR⁸R⁹, (t) heterocyclo other thanheteroaryl which is optionally substituted with one or more substituentsselected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, 4) (C₁-C₄)-perfluoroalkyl, 5) (C₂-C₆)-alkenyl, 6)(C₂-C₆)-alkynyl, 7) (C₁-C₆)-alkyloxy, 8) (C₁-C₆)-alkyl-S(O)_(n)—, 9)cyano, 10) —COOH, 11) —CO(C₁-C₆)-alkyl, 12) —CO₂(C₁-C₆)-alkyl, 13)—CONR⁸R⁹, 14) —NR⁸R⁹, 15) —O(C═O)—(C₁-C₆)-alkyl, and 16) —O(C═O)NR⁸R⁹,(u) benzyl-S(O)_(n)—, (v) (C₂-C₁₀)-alkenyl, which may optionally besubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) cyano, 6) —COOH, 7) —CO(C₁-C₆)-alkyl, 8)—CO₂(C₁-C₆)-alkyl, 9) —CONR⁸R⁹, 10) —NR⁸R⁹, 11) —O(C═O)—(C₁-C₆)-alkyl,and 12) —O(C═O)NR⁸R⁹, (w) (C₂-C₁₀)-alkynyl wherein alkynyl is optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) cyano, 6) —COOH, 7) —CO(C₁-C₆)-alkyl, 8)—CO₂(C₁-C₆)-alkyl, 9) —CONR⁸R⁹, 10) —NR⁸R⁹, 11) —O(C═O)—(C₁-C₆)-alkyl,and 12) —O(C═O)NR⁸R⁹, (x) —(C₁-C₁₀)-alkyl, which may optionally besubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) benzyl-S(O)_(n)—, 6) cyano, 7) —COOH, 8)—CO(C₁-C₆)-alkyl, 9) —CO₂(C₁-C₆)-alkyl, 10) —CONR⁸R⁹, 11) —NR⁸R⁹, 12)—O(C═O)—(C₁-C₆)-alkyl, and 13) —O(C═O)NR⁸R⁹; R¹¹ is: (a) halo, (b) —OH,(c) —O[(C═O)O_(r)]_(s)(C₁-C₆)-alkyl, (d)—O[(C═O)O_(r)]_(s)(C₂-C₆)-alkenyl, (e) —O[(C═O)O_(r)]_(s)aryl, (f)—O[(C═O)O_(r)]_(s)heteroaryl, (g) (C₁-C₆)-alkyl-S(O)_(n)—, (h)aryl-(C₁-C₆)alkyloxy-, (i) cyano, (j) —NR⁸R⁹, (k) —O(CO)NR⁸R⁹, (l)—COOH, (m) —CO(C₁-C₆)-alkyl, (n) —CO₂(C₁-C₆)-alkyl, (o) —CONR⁸R⁹, (p)aryl, which may optionally be substituted with one or more substituentsselected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, 4) aryl-(C₁-C₆)alkyloxy-, 5) (C₁-C₄)-perfluoroalkyl, 6)(C₂-C₆)-alkenyl, 7) (C₂-C₆)-alkynyl, 8) (C₁-C₆)-alkyloxy, 9)(C₁-C₆)-alkyl-S(O)_(n)—, 10) cyano, 11) —COOH, 12) —CO(C₁-C₆)-alkyl, 13)—CO₂(C₁-C₆)-alkyl, 14) —CONR⁸R⁹, 15) —NR⁸R⁹, 16) —O(C═O)—(C₁-C₆)-alkyl,and 17) —O(C═O)NR⁸R⁹, (q) heteroaryl optionally substituted with one ormore substituents selected from the group consisting of: 1) halo, 2)—OH, 3) (C₁-C₆)-alkyl, 4) aryl-(C₁-C₆)alkyloxy-, 5)(C₁-C₄)-perfluoroalkyl, 6) (C₂-C₆)-alkenyl, 7) (C₂-C₆)-alkynyl, 8)(C₁-C₆)-alkyloxy, 9) (C₁-C₆)-alkyl-S(O)_(n)—, 10) cyano, 11) —COOH, 12)—CO(C₁-C₆)-alkyl, 13) —CO₂(C₁-C₆)-alkyl, 14) —CONR⁸R⁹, 15) —NR⁸R⁹, 16)—O(C═O)—(C₁-C₆)-alkyl, and 17) —O(C═O)NR⁸R⁹, (r) heterocyclo other thanheteroaryl which is optionally substituted with one or more substituentsselected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, 4) aryl-(C₁-C₆)alkyloxy-, 5) (C₁-C₄)-perfluoroalkyl, 6)(C₂-C₆)-alkenyl, 7) (C₂-C₆)-alkynyl, 8) (C₁-C₆)-alkyloxy, 9)(C₁-C₆)-alkyl-S(O)_(n)—, 10) cyano, 11) —COOH, 12) —CO(C₁-C₆)-alkyl, 13)—CO₂(C₁-C₆)-alkyl, 14) —CONR⁸R⁹, 15) —NR⁸R⁹, 16) —O(C═O)—(C₁-C₆)-alkyl,and 17) —O(C═O)NR⁸R⁹, (s) —(C₂-C₁₀)-alkenyl, which may optionally besubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) phenyl-(C₁-C₆)-alkyloxy-, 6) cyano, 7) —CHO,8) —COOH, 9) —CO(C₁-C₆)-alkyl, 10) —CO₂(C₁-C₆)-alkyl, 11) —CONR⁸R⁹, 12)—NR⁸R⁹, 13) aryl, 14) heteroaryl as defined above, 15) heterocyclo otherthan heteroaryl as defined above, 16) —O(C═O)—(C₁-C₆)-alkyl, and 17)—O(C═O)NR⁸R⁹, (t) (C₂-C₁₀)-alkynyl wherein alkynyl is optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) phenyl-(C₁-C₆)-alkyloxy-, 6) cyano, 7)vinyl, 8) —CHO, 9) —COOH, 10) —CO(C₁-C₆)-alkyl, 11) —CO₂(C₁-C₆)-alkyl,12) —CONR⁸R⁹, 13) —NR⁸R⁹, 14) aryl, wherein aryl is defined as above,15) heteroaryl as defined above, 16) heterocyclyl other than heteroarylas defined above, 17) —O(C═O)—(C₁-C₆)-alkyl, and 18) —O(C═O)NR⁸R⁹, (u)—(C₁-C₁₀)-alkyl, which may optionally be substituted with one or moresubstituents selected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyloxy, 4) (C₁-C₆)-alkyl-S(O)_(n)—, 5) benzyl-S(O)_(n)—, 6)cyano, 7) —COOH, 8) —CO(C₁-C₆)-alkyl, 9) —CO₂(C₁-C₆)-alkyl, 10)—CONR⁸R⁹, 11) —NR⁸R⁹, 12) —O(C═O)—(C₁-C₆)-alkyl, and 13) —O(C═O)NR⁸R⁹,(v) —O(CH₂)_(m)-heteroaryl as defined above; R¹² is: (a) halo, (b) —OH,(c) —O[(C═O)O_(r)]_(s)(C₁-C₆)-alkyl, (d)—O[(C═O)O_(r)]_(s)(C₂-C₆)-alkenyl, (e) —O[(C═O)O_(r)]_(s)aryl, (f)—O[(C═O)O_(r)]_(s)heteroaryl, (g) (C₁-C₆)-alkyl-S(O)_(n)—, (h)aryl-(C₁-C₆)alkyloxy-, (i) cyano, (j) nitro, (k) —NR⁸R⁹, (l)—O(CO)NR⁸R⁹, (m) —CHO, (n) —COOH, (o) —CO(C₁-C₆)-alkyl, (p)—CO₂(C₁-C₆)-alkyl, (q) —CONR⁸R⁹, (r) aryl, which may optionally besubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, 4)(C₁-C₄)-perfluoroalkyl, 5) (C₂-C₆)-alkenyl, 6) (C₂-C₆)-alkynyl, 7)(C₁-C₆)-alkyloxy, 8) (C₁-C₆)-alkyl-S(O)_(n)—, 9) cyano, 10) —COOH, 11)—CO(C₁-C₆)-alkyl, 12) —CO₂(C₁-C₆)-alkyl, 13) —CONR⁸R⁹, 14) —NR⁸R⁹, 15)—O(C═O)—(C₁-C₆)-alkyl, and 16) —O(C═O)NR⁸R⁹, (s) heteroaryl optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, 4)(C₁-C₄)-perfluoroalkyl, 5) (C₂-C₆)-alkenyl, 6) (C₂-C₆)-alkynyl, 7)(C₁-C₆)-alkyloxy, 8) (C₁-C₆)-alkyl-S(O)_(n)—, 9) cyano, 10) —COOH, 11)—CO(C₁-C₆)-alkyl, 12) —CO₂(C₁-C₆)-alkyl, 13) —CONR⁸R⁹, 14) —NR⁸R⁹, 15)—O(C═O)—(C₁-C₆)-alkyl, and 16) —O(C═O)NR⁸R⁹, (t) heterocyclo other thanheteroaryl which is optionally substituted with one or more substituentsselected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, 4) (C₁-C₄)-perfluoroalkyl, 5) (C₂-C₆)-alkenyl, 6)(C₂-C₆)-alkynyl, 7) (C₁-C₆)-alkyloxy, 8) (C₁-C₆)-alkyl-S(O)_(n)—, 9)cyano, 10) —COOH, 11) —CO(C₁-C₆)-alkyl, 12) —CO₂(C₁-C₆)-alkyl, 13)—CONR⁸R⁹, 14) —NR⁸R⁹, 15) —O(C═O)—(C₁-C₆)-alkyl, and 16) —O(C═O)NR⁸R⁹,(u) benzyl-S(O)_(n)—, (v) (C₂-C₁₀)-alkenyl, which may optionally besubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) cyano, 6) —COOH, 7) —CO(C₁-C₆)-alkyl, 8)—CO₂(C₁-C₆)-alkyl, 9) —CONR⁸R⁹, 10) —NR⁸R⁹, 11) —O(C═O)—(C₁-C₆)-alkyl,and 12) —O(C═O)NR⁸R⁹, (w) (C₂-C₁₀)-alkynyl wherein alkynyl is optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) cyano, 6) —COOH, 7) —CO(C₁-C₆)-alkyl, 8)—CO₂(C₁-C₆)-alkyl, 9) —CONR⁸R⁹, 10) —NR⁸R⁹, 11) —O(C═O)—(C₁-C₆)-alkyl,and 12) —O(C═O)NR⁸R⁹, (x) —(C₁-C₁₀)-alkyl, which may optionally besubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) benzyl-S(O)_(n)—, 6) cyano, 7) —COOH, 8)—CO(C₁-C₆)-alkyl, 9) —CO₂(C₁-C₆)-alkyl, 10) —CONR⁸R⁹, 11) —NR⁸R⁹, 12)—O(C═O)—(C₁-C₆)-alkyl, and 13) —O(C═O)NR⁸R⁹, y) ═O; R¹⁴ is: (a) halo,(b) —OH, (c) —O[(C═O)O_(r)]_(s)(C₁-C₆)-alkyl, (d)—O[(C═O)O_(r)]_(s)(C₂-C₆)-alkenyl, (e) —O[(C═O)O_(r)]_(s)aryl, (f)—O[(C═O)O_(r)]_(s)heteroaryl, (g) (C₁-C₆)-alkyl-S(O)_(n)—, (h)aryl-(C₁-C₆)alkyloxy-, (i) cyano, (j) nitro, (k) —NR⁸R⁹, (l)—O(CO)NR⁸R⁹, (m) —CHO, (n) —COOH, (o) —CO(C₁-C₆)-alkyl, (p)—CO₂(C₁-C₆)-alkyl, (q) —CONR⁸R⁹, (r) aryl, which may optionally besubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, 4)(C₁-C₄)-perfluoroalkyl, 5) (C₂-C₆)-alkenyl, 6) (C₂-C₆)-alkynyl, 7)(C₁-C₆)-alkyloxy, 8) (C₁-C₆)-alkyl-S(O)_(n)—, 9) cyano, 10) —COOH, 11)—CO(C₁-C₆)-alkyl, 12) —CO₂(C₁-C₆)-alkyl, 13) —CONR⁸R⁹, 14) —NR⁸R⁹, 15)—O(C═O)—(C₁-C₆)-alkyl, and 16) —O(C═O)NR⁸R⁹, (s) heteroaryl optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, 4)(C₁-C₄)-perfluoroalkyl, 5) (C₂-C₆)-alkenyl, 6) (C₂-C₆)-alkynyl, 7)(C₁-C₆)-alkyloxy, 8) (C₁-C₆)-alkyl-S(O)_(n)—, 9) cyano, 10) —COOH, 11)—CO(C₁-C₆)-alkyl, 12) —CO₂(C₁-C₆)-alkyl, 13) —CONR⁸R⁹, 14) —NR⁸R⁹, 15)—O(C═O)—(C₁-C₆)-alkyl, and 16) —O(C═O)NR⁸R⁹, (t) heterocyclo other thanheteroaryl which is optionally substituted with one or more substituentsselected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, 4) (C₁-C₄)-perfluoroalkyl, 5) (C₂-C₆)-alkenyl, 6)(C₂-C₆)-alkynyl, 7) (C₁-C₆)-alkyloxy, 8) (C₁-C₆)-alkyl-S(O)_(n)—, 9)cyano, 10) —COOH, 11) —CO(C₁-C₆)-alkyl, 12) —CO₂(C₁-C₆)-alkyl, 13)—CONR⁸R⁹, 14) —NR⁸R⁹, 15) —O(C═O)—(C₁-C₆)-alkyl, and 16) —O(C═O)NR⁸R⁹,(u) benzyl-S(O)_(n)—, (v) (C₂-C₁₀)-alkenyl, which may optionally besubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) cyano, 6) —COOH, 7) —CO(C₁-C₆)-alkyl, 8)—CO₂(C₁-C₆)-alkyl, 9) —CONR⁸R⁹, 10) —NR⁸R⁹, 11) —O(C═O)—(C₁-C₆)-alkyl,and 12) —O(C═O)NR⁸R⁹, (w) (C₂-C₁₀)-alkynyl wherein alkynyl is optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) cyano, 6) —COOH, 7) —CO(C₁-C₆)-alkyl, 8)—CO₂(C₁-C₆)-alkyl, 9) —CONR⁸R⁹, 10) —NR⁸R⁹, 11) —O(C═O)—(C₁-C₆)-alkyl,and 12) —O(C═O)NR⁸R⁹, (x) —(C₁-C₁₀)-alkyl, which may optionally besubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) benzyl-S(O)_(n)—, 6) cyano, 7) —COOH, 8)—CO(C₁-C₆)-alkyl, 9) —CO₂(C₁-C₆)-alkyl, 10) —CONR⁸R⁹, 11) —NR⁸R⁹, 12)—O(C═O)—(C₁-C₆)-alkyl, and 13) —O(C═O)NR⁸R⁹; R¹⁶ and R¹⁷ areindependently: (a) aryl, which may optionally be substituted with one ormore substituents selected from the group consisting of: 1) halo, 2)—OH, 3) (C₁-C₆)-alkyl, 4) (C₁-C₄)-perfluoroalkyl, 5) (C₂-C₆)-alkenyl, 6)(C₂-C₆)-alkynyl, 7) (C₁-C₆)-alkyloxy, 8) (C₁-C₆)-alkyl-S(O)_(n)—, 9)cyano, 10) —COOH, 11) —CO(C₁-C₆)-alkyl, 12) —CO₂(C₁-C₆)-alkyl, 13)—CONR⁸R⁹, 14) —NR⁸R⁹, 15) —O(C═O)—(C₁-C₆)-alkyl, and 16) —O(C═O)NR⁸R⁹,(b) heteroaryl optionally substituted with one or more substituentsselected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, 4) (C₁-C₄)-perfluoroalkyl, 5) (C₂-C₆)-alkenyl, 6)(C₂-C₆)-alkynyl, 7) (C₁-C₆)-alkyloxy, 8) (C₁-C₆)-alkyl-S(O)_(n)—, 9)cyano, 10) —COOH, 11) —CO(C₁-C₆)-alkyl, 12) —CO₂(C₁-C₆)-alkyl, 13)—CONR⁸R⁹, 14) —NR⁸R⁹, 15) —O(C═O)—(C₁-C₆)-alkyl, and 16) —O(C═O)NR⁸R⁹,(c) heterocyclo other than heteroaryl which is optionally substitutedwith one or more substituents selected from the group consisting of: 1)halo, 2) —OH, 3) (C₁-C₆)-alkyl, 4) (C₁-C₄)-perfluoroalkyl, 5)(C₂-C₆)-alkenyl, 6) (C₂-C₆)-alkynyl, 7) (C₁-C₆)-alkyloxy, 8)(C₁-C₆)-alkyl S(O)_(n)—, 9) cyano, 10) —COOH, 11) —CO(C₁-C₆)-alkyl, 12)—CO₂(C₁-C₆)-alkyl, 13) —CONR⁸R⁹, 14) —NR⁸R⁹, 15) —O(C═O)—(C₁-C₆)-alkyl,and 16) —O(C═O)NR⁸R⁹, (d) (C₂-C₁₀)-alkenyl, which may optionally besubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) cyano, 6) —COOH, 7) —CO(C₁-C₆)-alkyl, 8)—CO₂(C₁-C₆)-alkyl, 9) —CONR⁸R⁹, 10) —NR⁸R⁹, 11) —O(C═O)—(C₁-C₆)-alkyl,and 12) —O(C═O)NR⁸R⁹, (e) (C₂-C₁₀)-alkynyl wherein alkynyl is optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) cyano, 6) —COOH, 7) —CO(C₁-C₆)-alkyl, 8)—CO₂(C₁-C₆)-alkyl, 9) —CONR⁸R⁹, 10) —NR⁸R⁹, 11) —O(C═O)—(C₁-C₆)-alkyl,and 12) —O(C═O)NR⁸R⁹, (f) —(C₁-C₁₀)-alkyl, which may optionally besubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) benzyl-S(O)_(n)—, 6) cyano, 7) —COOH, 8)—CO(C₁-C₆)-alkyl, 9) —CO₂(C₁-C₆)-alkyl, 10) —CONR⁸R⁹, 11) —NR⁸R⁹, 12)—O(C═O)—(C₁-C₆)-alkyl, and 13) —O(C═O)NR⁸R⁹, or R¹⁶ and R¹⁷ are takentogether with the nitrogen to which both are attached to form a 3- to8-membered ring, which may optionally contain 1-4 heteroatoms selectedfrom N, O, and S and be optionally substituted with one or more R¹⁴'s;R¹⁸ is cyano, —COR¹⁶ or —SO₂R¹⁶; R¹⁹ is: (a) hydrogen, (b)(C₁-C₆)-alkyl, (c) —CO(C₁-C₆)-alkyl, (d) —CO(C₁-C₆)-aryl, (e)—CO(C₁-C₆)-heteroaryl, (f) —CO₂(C₁-C₆)-alkyl, (g) CO₂(C₁-C₆)-aryl, (h)CO₂(C₁-C₆)-heteroaryl, (i) —CONR⁸R⁹, (j) —S(O)_(n)-alkyl, (k)—S(O)_(n)-aryl, (l) —S(O)_(n)-heteroaryl, or (m) —S(O)_(n)—NR⁸R⁹; R²⁰ isindependently: (a) hydrogen, (b) halo, (c) —OH, (d)—O[(C═O)O_(r)]_(s)(C₁-C₆)-alkyl, (e) —O[(C═O)O_(r)]_(s)(C₂-C₆)-alkenyl,(f) —O[(C═O)O_(r)]_(s)aryl, (g) —O[(C═O)O_(r)]_(s)heteroaryl, (h)(C₁-C₆)-alkyl-S(O)_(n)—, (i) aryl-(C₁-C₆)alkyloxy-, (j) cyano, (k)nitro, (l) —NR⁸R⁹ (m) O(CO)NR⁸R⁹, (n) —CHO, (o) COOH, (p)—CO(C₁-C₆)-alkyl, (q) —CO₂(C₁-C₆)-alkyl, (r) —CONR⁸R⁹, (s) aryl, whichmay optionally be substituted with one or more substituents selectedfrom the group consisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, 4)(C₁-C₄)-perfluoroalkyl, 5) (C₂-C₆)-alkenyl, 6) (C₂-C₆)-alkynyl, 7)(C₁-C₆)-alkyloxy, 8) (C₁-C₆)-alkyl-S(O)_(n)—, 9) cyano, 10) —COOH, 11)—CO(C₁-C₆)-alkyl, 12) —CO₂(C₁-C₆)-alkyl, 13) —CONR⁸R⁹, 14) —NR⁸R⁹, 15)—O(C═O)—(C₁-C₆)-alkyl, and 16) —O(C═O)NR⁸R⁹, (t) heteroaryl optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyl, 4)(C₁-C₄)-perfluoroalkyl, 5) (C₂-C₆)-alkenyl, 6) (C₂-C₆)-alkynyl, 7)(C₁-C₆)-alkyloxy, 8) (C₁-C₆)-alkyl-S(O)_(n)—, 9) cyano, 10) —COOH, 11)—CO(C₁-C₆)-alkyl, 12) —CO₂(C₁-C₆)-alkyl, 13) —CONR⁸R⁹, 14) —NR⁸R⁹, 15)—O(C═O)—(C₁-C₆)-alkyl, and 16) —O(C═O)NR⁸R⁹, (u) heterocyclo other thanheteroaryl which is optionally substituted with one or more substituentsselected from the group consisting of: 1) halo, 2) —OH, 3)(C₁-C₆)-alkyl, 4) (C₁-C₄)-perfluoroalkyl, 5) (C₂-C₆)-alkenyl, 6)(C₂-C₆)-alkynyl, 7) (C₁-C₆)-alkyloxy, 8) (C₁-C₆)-alkyl-S(O)_(n)—, 9)cyano, 10) —COOH, 11) —CO(C₁-C₆)-alkyl, 12) —CO₂(C₁-C₆)-alkyl, 13)—CONR⁸R⁹, 14) —NR⁸R⁹, 15) —O(C═O)—(C₁-C₆)-alkyl, and 16) —O(C═O)NR⁸R⁹,(v) benzyl-S(O)_(n)—, (w) (C₂-C₁₀)-alkenyl, which may optionally besubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) cyano, 6) —COOH, 7) —CO(C₁-C₆)-alkyl, 8)—CO₂(C₁-C₆)-alkyl, 9) —CONR⁸R⁹, 10) —NR⁸R⁹, 11) —O(C═O)—(C₁-C₆)-alkyl,and 12) —O(C═O)NR⁸R⁹, (x) (C₂-C₁₀)-alkynyl wherein alkynyl is optionallysubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) cyano, 6) —COOH, 7) —CO(C₁-C₆)-alkyl, 8)—CO₂(C₁-C₆)-alkyl, 9) —CONR⁸R⁹, 10) —NR⁸R⁹, 11) —O(C═O)—(C₁-C₆)-alkyl,and 12) —O(C═O)NR⁸R⁹, (y) —(C₁-C₁₀)-alkyl, which may optionally besubstituted with one or more substituents selected from the groupconsisting of: 1) halo, 2) —OH, 3) (C₁-C₆)-alkyloxy, 4)(C₁-C₆)-alkyl-S(O)_(n)—, 5) benzyl-S(O)_(n)—, 6) cyano, 7) —COOH, 8)—CO(C₁-C₆)-alkyl, 9) —CO₂(C₁-C₆)-alkyl, 10) —CONR⁸R⁹, 11) —NR⁸R⁹, 12)—O(C═O)—(C₁-C₆)-alkyl, and 13) —O(C═O)NR⁸R⁹; R²¹ is: (a) C₁-C₁₀-alkyloptionally substituted with one or more R¹¹'s, (b) C₃-C₈-cycloalkyloptionally substituted with one or more R¹¹'s, (c) aryl optionallysubstituted with one or more R¹¹'s, or (d) heterocyclyl optionallysubstituted with one or more R¹¹'s; m is 1 to 5; n is 0 to 3; p is 1 or2; r is 0 to 5; and s is 0 to 4.